Biaryl kinase inhibitors

ABSTRACT

The present disclosure is generally directed to compounds which can inhibit AAK1 (adaptor associated kinase 1), compositions comprising such compounds, and methods for inhibiting AAK1.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Continuation application claims the benefit of U.S. Ser. No.16/443,929, filed Jun. 18, 2019, now allowed, which claims the benefitof U.S. Ser. No. 16/168,533, filed Oct. 23, 2018, now U.S. Pat. No.10,351,563, which claims the benefit of U.S. Ser. No. 15/865,848 filedJan. 9, 2018, now U.S. Pat. No. 10,155,760, which claims the benefit ofU.S. Ser. No. 15/300,618 filed Sep. 29, 2016, now U.S. Pat. No.9,902,722, which is a 371 of PCT/US2015/023805 filed Apr. 1, 2015, whichclaims the benefit of Provisional application U.S. Ser. No. 61/973,942filed Apr. 2, 2014, and Provisional application U.S. Ser. No. 62/061,591filed Oct. 8, 2014, hereby incorporated by reference in theirentireties.

The present disclosure is generally directed to compounds which caninhibit adaptor associated kinase 1 (AAK1), compositions comprising suchcompounds, and methods for inhibiting AAK1.

Adaptor associated kinase 1 (AAK1) is a member of the Ark1/Prk1 familyof serine/threonine kinases. AAK1 mRNA exists in two splice forms termedshort and long. The long form predominates and is highly expressed inbrain and heart (Henderson and Conner, Mol. Biol. Cell. 2007, 18,2698-2706). AAK1 is enriched in synaptosomal preparations and isco-localized with endocytic structures in cultured cells. AAK1 modulatesclatherin coated endocytosis, a process that is important in synapticvesicle recycling and receptor-mediated endocytosis. AAK1 associateswith the AP2 complex, a hetero-tetramer which links receptor cargo tothe clatherin coat. The binding of clatherin to AAK1 stimulates AAK1kinase activity (Conner et. al., Traffic 2003, 4, 885-890; Jackson et.al., J. Cell. Biol. 2003, 163, 231-236). AAK1 phosphorylates the mu-2subunit of AP-2, which promotes the binding of mu-2 to tyrosinecontaining sorting motifs on cargo receptors (Ricotta et. al., J. CellBio. 2002, 156, 791-795; Conner and Schmid, J. Cell Bio. 2002, 156,921-929). Mu2 phosphorylation is not required for receptor uptake, butphosphorylation enhances the efficiency of internalization (Motely et.al., Mol. Biol. Cell. 2006, 17, 5298-5308).

AAK1 has been identified as an inhibitor of Neuregulin-1/ErbB4 signalingin PC12 cells. Loss of AAK1 expression through RNA interference mediatedgene silencing or treatment with the kinase inhibitor K252a (whichinhibits AAK1 kinase activity) results in the potentiation ofNeuregulin-1 induced neurite outgrowth. These treatments result inincreased expression of ErbB4 and accumulation of ErbB4 in or near theplasma membrane (Kuai et. al., Chemistry and Biology 2011, 18, 891-906).NRG1 and ErbB4 are putative schizophrenia susceptibility genes(Buonanno, Brain Res. Bull. 2010, 83, 122-131). SNPs in both genes havebeen associated with multiple schizophrenia endophenotypes (Greenwoodet. al., Am. J. Psychiatry 2011, 168, 930-946). Neuregulin 1 and ErbB4KO mouse models have shown schizophrenia relevant morphological changesand behavioral phenotypes (Jaaro-Peled et. al., Schizophrenia Bulletin2010, 36, 301-313; Wen et. al., Proc. Natl. Acad. Sci. USA. 2010, 107,1211-1216). In addition, a single nucleotide polymorphism in an intronof the AAK1 gene has been associated with the age of onset ofParkinson's disease (Latourelle et. al., BMC Med. Genet. 2009, 10, 98).These results suggest that inhibition of AAK1 activity may have utilityin the treatment of schizophrenia, cognitive deficits in schizophrenia,Parkinson's disease, neuropathic pain, bipolar disorder, and Alzheimer'sdisease.

In addition, studies using Huh-7.5 cells indicate a potential utilityfor AAK1 kinase inhibitors in the treatment of hepatitis C (HCV)infection. Reduction of AAK1 protein using RNA interference mediatedgene silencing, treatment with the kinase inhibitor sunitinib (a potentAAK1 inhibitor), and overexpression of Mu2 (AAK1 substrate)phosphorylation site mutant all result in reduced HCV virion assembly.Furthermore the same treatments were shown to inhibit HCV entry,suggesting AAK1 inhibitors can disrupt two host dependent stages of thevirus life cycle (Neveu et. al., PLoS Pathog. 2012, 8, 1-16; Neveu et.al., J. Virol. 2015, posted online 4 February). AAK1 inhibitors may alsobe useful against HIV and HBV (see, for example, Boge et al., J. Biol.Chem. 1998, 273, 15773-15778).

In its first aspect the present disclosure provides a compound offormula (I) A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

A is selected from

wherein “

” denotes the point of attachment to B;

B is selected from

wherein “*” indicates the point of attachment to R5 and “**” indicatesthe point of attachment to ring A;

R¹ is selected from hydrogen, amino, —CO₂H, difluoromethyl, ethyl, halo,hydroxymethyl, methoxy, methyl, —NHC(O)CH₃, —NHCO₂CH₃, trifluoromethoxy,and trifluoromethyl;

R² is selected from hydrogen, cyano, —CH₂OH, halo, and methyl;

R³ is selected from hydrogen, cyano, cyclopropyl, difluoromethyl, halo,hydroxymethyl, methoxy, methyl, methylsulfonyl, trifluoromethoxy,trifluoromethyl, —CH₂N(CH₃)₂, and a five-membered aromatic ringcontaining one, two, or three heteroatoms selected from nitrogen,oxygen, and sulfur;

R⁴ is selected from hydrogen, halo, and methyl;

R⁵ is selected from

R⁶ is selected from hydrogen, ethyl, fluoromethyl, difluoromethyl,methyl, and trifluoromethyl; and

R⁷ is methyl.

In a first embodiment of the first aspect the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein A is selected from

In a second embodiment of the first aspect the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein B is selected from

In a third embodiment, B is.

In a fourth embodiment of the first aspect the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein R⁵ is

In a second aspect the present disclosure provides a compound of formula(II)

or a pharmaceutically acceptable salt thereof, wherein:

A is selected from

wherein “

” denotes the point of attachment to B;

B is selected from phenyl and pyridinyl;

R¹ is selected from hydrogen, difluoromethyl, halo, methoxy, methyl,—NHC(O)CH₃, —NHCO₂CH₃, and trifluoromethyl;

R² is selected from hydrogen, —CH₂OH, and halo;

R³ is selected from hydrogen, cyano, cyclopropyl, difluoromethyl, halo,hydroxymethyl, methoxy, methyl, trifluoromethoxy, trifluoromethyl, and afive-membered aromatic ring containing one, two, or three heteroatomsselected from nitrogen, oxygen, and sulfur;

R⁴ is selected from hydrogen, halo, and methyl; and

R⁵ is selected from hydrogen, ethyl, fluoromethyl, difluoromethyl,methyl, and trifluoromethyl.

In a first embodiment of the second aspect the present disclosureprovides a compound of formula (II), or a pharmaceutically acceptablesalt thereof, wherein A is selected from

In a second embodiment of the second aspect the present disclosureprovides a compound of formula (II), or a pharmaceutically acceptablesalt thereof, wherein B is pyridinyl. In a third embodiment B is.

wherein “

” denotes the point of attachment to A and “

” denotes the point of attachment to the oxygen atom.

In a fourth embodiment of the second aspect the present disclosureprovides a compound of formula (II), or a pharmaceutically acceptablesalt thereof, wherein wherein

A is selected from

and

B is

In a third aspect the present disclosure provides a compositioncomprising a pharmaceutically acceptable amount of a compound of formula(I), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

In a fourth aspect the present disclosure provides a method ofinhibiting adaptor associated kinase 1 (AAK1) activity, comprisingcontacting AAK1 with a compound of formula (I), or a pharmaceuticallyacceptable salt thereof.

In a fifth aspect the present disclosure provides a method for treatingor managing a disease or a disorder mediated by AAK1 activity, themethod comprising administering to a patient in need thereof atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof. In a first embodiment of thefifth aspect the disease or disorder is selected from Alzheimer'sdisease, bipolar disorder, pain, Parkinson's disease, and schizophrenia.In a second embodiment the pain is neuropathic pain. In a thirdembodiment the neuropathic pain is fibromyalgia or peripheralneuropathy.

Other aspects of the present disclosure may include suitablecombinations of embodiments disclosed herein.

Yet other aspects and embodiments may be found in the descriptionprovided herein.

BRIEF DESCRIPTION OF THE FIGURES

Aspects of the disclosure are illustrated in FIG. 1, which shows resultsobtained from a formalin pain model using AAK1 homozygous (−/−) knockoutmice and their wild-type (+/+) littermates. The AAK1 homozygous (−/−)knockout mice show a clear reduction in both acute and tonic painresponse as compared to their wild-type (+/+) littermates.

This disclosure is based, in part, on the discovery that AAK1 knockoutmice exhibit a high resistance to pain. That discovery prompted researchthat ultimately led to the discovery of AAK1 inhibitors, compositionscomprising them, and methods of their use.

The description of the present disclosure herein should be construed incongruity with the laws and principals of chemical bonding. In someinstances it may be necessary to remove a hydrogen atom in order toaccommodate a substituent at any given location.

It should be understood that the compounds encompassed by the presentdisclosure are those that are suitably stable for use as pharmaceuticalagent.

As used in the present specification, the following terms have themeanings indicated:

All patents, patent applications, and literature references cited in thespecification are herein incorporated by reference in their entirety. Inthe case of inconsistencies, the present disclosure, includingdefinitions, will prevail.

As used herein, the singular forms “a”, “an”, and “the” include pluralreference unless the context clearly dictates otherwise.

In some instances, the number of carbon atoms in any particular group isdenoted before the recitation of the group. For example, the term “C₁₋₆alkyl” denotes an alkyl group containing one to six carbon atoms. Wherethese designations exist they supercede all other definitions containedherein.

The term “halo,” as used herein, refers to Br, Cl, F, and/or I.

Asymmetric centers may exist in the compounds of the present disclosure.It should be understood that the disclosure encompasses allstereochemical isomeric forms, or mixtures thereof, which possess theability to inhibit AAK1. Individual stereoisomers of compounds can beprepared synthetically from commercially available starting materialswhich contain chiral centers or by preparation of mixtures ofenantiomeric products followed by separation such as conversion to amixture of diastereomers followed by separation or recrystallization,chromatographic techniques, or direct separation of enantiomers onchiral chromatographic columns. Starting compounds of particularstereochemistry are either commercially available or can be made andresolved by techniques known in the art.

Certain compounds of the present disclosure may also exist in differentstable conformational forms which may be separable. Torsional asymmetrydue to restricted rotation about an asymmetric single bond, for examplebecause of steric hindrance or ring strain, may permit separation ofdifferent conformers. The present disclosure includes eachconformational isomer of these compounds and mixtures thereof.

The term “compounds of the present disclosure”, and equivalentexpressions, are meant to embrace compounds of formula (I), andpharmaceutically acceptable enantiomers, diastereomers, and saltsthereof. Similarly, references to intermediates are meant to embracetheir salts where the context so permits.

The present disclosure is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the disclosure can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds may have a variety of potential uses,for example as standards and reagents in determining biologicalactivity. In the case of stable isotopes, such compounds may have thepotential to favorably modify biological, pharmacological, orpharmacokinetic properties.

The compounds of the present disclosure can exist as pharmaceuticallyacceptable salts. The term “pharmaceutically acceptable salt,” as usedherein, represents salts or zwitterionic forms of the compounds of thepresent disclosure which are water or oil-soluble or dispersible, whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of patients without excessive toxicity,irritation, allergic response, or other problem or complicationcommensurate with a reasonable benefit/risk ratio, and are effective fortheir intended use. The salts can be prepared during the final isolationand purification of the compounds or separately by reacting a suitablenitrogen atom with a suitable acid. Representative acid addition saltsinclude acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate;digluconate, dihydrobromide, diydrochloride, dihydroiodide,glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate,hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,lactate, maleate, mesitylenesulfonate, methanesulfonate,naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,palmoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate,propionate, succinate, tartrate, trichloroacetate, trifluoroacetate,phosphate, glutamate, bicarbonate, para-toluenesulfonate, andundecanoate. Examples of acids which can be employed to formpharmaceutically acceptable addition salts include inorganic acids suchas hydrochloric, hydrobromic, sulfuric, and phosphoric, and organicacids such as oxalic, maleic, succinic, and citric.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of pharmaceutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,and N,N′-dibenzylethylenediamine. Other representative organic aminesuseful for the formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, and piperazine.

One embodiment of this disclosure encompasses methods of inhibitingadaptor associated kinase 1 (AAK1), both in vitro and in vivo, whichcomprise contacting AAK1 with a compound of formula I or apharmaceutically acceptable salt thereof.

When it is possible that, for use in therapy, therapeutically effectiveamounts of a compound of formula (I), as well as pharmaceuticallyacceptable salts thereof, may be administered as the raw chemical, it ispossible to present the active ingredient as a pharmaceuticalcomposition. Accordingly, the disclosure further provides pharmaceuticalcompositions, which include therapeutically effective amounts ofcompounds of formula (I) or pharmaceutically acceptable salts thereof,and one or more pharmaceutically acceptable carriers, diluents, orexcipients. Unless otherwise indicated, a “therapeutically effectiveamount” of a compound is an amount sufficient to provide a therapeuticbenefit in the treatment or management of a disease or condition, or todelay or minimize one or more symptoms associated with the disease orcondition. The term “therapeutically effective amount” can encompass anamount that improves overall therapy, reduces or avoids symptoms orcauses of a disease or condition, or enhances the therapeutic efficacyof another therapeutic agent.

The term “therapeutically effective amount,” as used herein, refers toan amount of a compound or compounds sufficient to provide a therapeuticbenefit in the treatment or management of a disease or condition, or todelay or minimize one or more symptoms associated with the disease orcondition. A “therapeutically effective amount” of a compound means anamount of therapeutic agent, alone or in combination with othertherapies, that provides a therapeutic benefit in the treatment ormanagement of the disease or condition. The term “therapeuticallyeffective amount” can encompass an amount that improves overall therapy,reduces or avoids symptoms or causes of a disease or condition, orenhances the therapeutic efficacy of another therapeutic agent. Whenapplied to an individual active ingredient, administered alone, the termrefers to that ingredient alone. When applied to a combination, the termrefers to combined amounts of the active ingredients that result in thetherapeutic effect, whether administered in combination, serially, orsimultaneously. The compounds of formula (I) and pharmaceuticallyacceptable salts thereof, are as described above. The carrier(s),diluent(s), or excipient(s) must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof. In accordance with another aspectof the present disclosure there is also provided a process for thepreparation of a pharmaceutical formulation including admixing acompound of formula (I), or a pharmaceutically acceptable salt thereof,with one or more pharmaceutically acceptable carriers, diluents, orexcipients. The term “pharmaceutically acceptable,” as used herein,refers to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of patients without excessive toxicity,irritation, allergic response, or other problem or complicationcommensurate with a reasonable benefit/risk ratio, and are effective fortheir intended use.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Dosage levels of between about 0.01 and about 250 milligram per kilogram(“mg/kg”) body weight per day, preferably between about 0.05 and about100 mg/kg body weight per day of the compounds of the present disclosureare typical in a monotherapy for the prevention and treatment ofdisease. Typically, the pharmaceutical compositions of this disclosurewill be administered from about 1 to about 5 times per day oralternatively, as a continuous infusion. Such administration can be usedas a chronic or acute therapy. The amount of active ingredient that maybe combined with the carrier materials to produce a single dosage formwill vary depending on the condition being treated, the severity of thecondition, the time of administration, the route of administration, therate of excretion of the compound employed, the duration of treatment,and the age, gender, weight, and condition of the patient. Preferredunit dosage formulations are those containing a daily dose or sub-dose,as herein above recited, or an appropriate fraction thereof, of anactive ingredient. Treatment may be initiated with small dosagessubstantially less than the optimum dose of the compound. Thereafter,the dosage is increased by small increments until the optimum effectunder the circumstances is reached. In general, the compound is mostdesirably administered at a concentration level that will generallyafford effective results without causing any harmful or deleterious sideeffects.

When the compositions of this disclosure comprise a combination of acompound of the present disclosure and one or more additionaltherapeutic or prophylactic agent, both the compound and the additionalagent are usually present at dosage levels of between about 10 to 150%,and more preferably between about 10 and 80% of the dosage normallyadministered in a monotherapy regimen.

Compounds of the disclosure may be administered in combination with oneor more additional therapeutic or prophylactic agents. For example, whenused for the treatment of pain, possible additional agents includeimmunosuppressive agents, anti-inflammatory agents, and/or other agentsused in the treatment of pain.

Immunosuppressants suitable for use in the methods and compositions ofthis disclosure include those known in the art. Examples includeaminopterin, azathioprine, cyclosporin A, D-penicillamine, gold salts,hydroxychloroquine, leflunomide, methotrexate, minocycline, rapamycin,sulfasalazine, tacrolimus (FK506), and pharmaceutically acceptable saltsthereof. A particular immunosuppressant is methotrexate.

Additional examples of immunosuppressants include anti-TNF antibodies,such as adalimumab, certolizumab pegol, etanercept, and infliximab.Others include interleukin-1 blockers, such as anakinra. Others includeanti-B cell (CD20) antibodies, such as rituximab. Others include T cellactivation blockers, such as abatacept.

Other immunosuppressants include inosine monophosphate dehydrogenaseinhibitors, such as mycophenolate mofetil (CellCept®) and mycophenolicacid (Myfortic®).

Anti-inflammatory drugs suitable for use in the methods and compositionsof this disclosure include those known in the art. Examples includeglucocorticoids and NSAIDs. Examples of glucocorticoids includealdosterone, beclometasone, betamethasone, cortisone,deoxycorticosterone, dexamethasone, fludrocortisones, hydrocortisone,methylprednisolone, prednisolone, prednisone, triamcinolone, andpharmaceutically acceptable salts thereof.

Examples of NSAID include salicylates (e.g., aspirin, amoxiprin,benorilate, choline magnesium salicylate, diflunisal, faislamine, methylsalicylate, magnesium salicylate, salicyl salicylate, andpharmaceutically acceptable salts thereof), arylalkanoic acids (e.g.,diclofenac, aceclofenac, acemetacin, bromfenac, etodolac, indometacin,nabumetone, sulindac, tolmetin, and pharmaceutically acceptable saltsthereof), arylpropionic acids (e.g., ibuprofen, carprofen, fenbufen,fenoprofen, flurbiprofen, ketoprofen, ketorolac, loxoprofen, naproxen,oxaprozin, tiaprofenic acid, suprofen, and pharmaceutically acceptablesalts thereof), arylanthranilic acids (e.g., meclofenamic acid,mefenamic acid, and pharmaceutically acceptable salts thereof),pyrazolidine derivatives (e.g., azapropazone, metamizole,oxyphenbutazone, phenylbutazone, sulfinprazone, and pharmaceuticallyacceptable salts thereof), oxicams (e.g., lornoxicam, meloxicam,piroxicam, tenoxicam, and pharmaceutically acceptable salts thereof),COX-2 inhibitors (e.g., celecoxib, etoricoxib, lumiracoxib, parecoxib,rofecoxib, valdecoxib, and pharmaceutically acceptable salts thereof),and sulphonanilides (e.g., nimesulide and pharmaceutically acceptablesalts thereof).

Other agents used in the treatment of pain (including but not limited toneuropathic and inflammatory pain) include, but are not limited to,agents such as pregabalin, lidocaine, duloxetine, gabapentin,carbamazepine, capsaicin, and other serotonin/norepinephrine/dopaminereuptake inhibitors, and opiates (such as oxycontin, morphine, andcodeine).

In the treatment of pain caused by a known disease or condition, such asdiabetes, infection (e.g., herpes zoster or HIV infection), or cancer,compounds of the disclosure may be administered in combination with oneor more additional therapeutic or prophylactic agents directed at theunderlying disease or condition. For example, when used to treatdiabetic neuropathy, compounds of the disclosure may be administered incombination with one or more anti-diabetic agents, anti-hyperglycemicagents, hypolipidemic/lipid lowering agents, anti-obesity agents,anti-hypertensive agents and appetite suppressants. Examples ofanti-diabetic agents include biguanides (e.g., metformin, phenformin),glucosidase inhibitors (e.g., acarbose, miglitol), insulins (includinginsulin secretagogues and insulin sensitizers), meglitinides (e.g.,repaglinide), sulfonylureas (e.g., glimepiride, glyburide, gliclazide,chlorpropamide, and glipizide), biguanide/glyburide combinations (e.g.,Glucovance), thiazolidinediones (e.g., troglitazone, rosiglitazone, andpioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, PPARalpha/gamma dual agonists, glycogen phosphorylase inhibitors, inhibitorsof fatty acid binding protein (aP2), glucagon-like peptide-1 (GLP-1) orother agonists of the GLP-1 receptor, dipeptidyl peptidase IV (DPP4)inhibitors, and sodium-glucose co-transporter 2 (SGLT2) inhibitors(e.g., dapagliflozin, canagliflozin, and LX-4211).

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual, ortransdermal), vaginal, or parenteral (including subcutaneous,intracutaneous, intramuscular, intra-articular, intrasynovial,intrasternal, intrathecal, intralesional, intravenous, or intradermalinjections or infusions) route. Such formulations may be prepared by anymethod known in the art of pharmacy, for example by bringing intoassociation the active ingredient with the carrier(s) or excipient(s).Oral administration or administration by injection are preferred.

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilemulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water, and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing, and coloringagent can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate, or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate, or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents, and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, and the like. Lubricantsused in these dosage forms include sodium oleate, sodium chloride, andthe like. Disintegrators include, without limitation, starch, methylcellulose, agar, betonite, xanthan gum, and the like. Tablets areformulated, for example, by preparing a powder mixture, granulating orslugging, adding a lubricant and disintegrant, and pressing intotablets. A powder mixture is prepared by mixing the compound, suitablecomminuted, with a diluent or base as described above, and optionally,with a binder such as carboxymethylcellulose, an aliginate, gelating, orpolyvinyl pyrrolidone, a solution retardant such as paraffin, aresorption accelerator such as a quaternary salt and/or and absorptionagent such as betonite, kaolin, or dicalcium phosphate. The powdermixture can be granulated by wetting with a binder such as syrup, starchpaste, acadia mucilage, or solutions of cellulosic or polymericmaterials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc, ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present disclosure can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material, and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups, and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic vehicle. Solubilizers andemulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylenesorbitol ethers, preservatives, flavor additive such as peppermint oilor natural sweeteners, or saccharin or other artificial sweeteners, andthe like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax, or the like.

The compounds of formula (I), and pharmaceutically acceptable saltsthereof, can also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesicles,and multilamellar vesicles. Liposomes can be formed from a variety ofphopholipids, such as cholesterol, stearylamine, or phophatidylcholines.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may also be delivered by the use of monoclonal antibodies asindividual carriers to which the compound molecules are coupled. Thecompounds may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research 1986,3(6), 318.

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols, or oils.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a course powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e., by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or nasal drops, include aqueous or oilsolutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurized aerosols, nebulizers, orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams, or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats, and soutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders,granules, and tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavoringagents.

The term “patient” includes both human and other mammals. Unlessotherwise indicated, the terms “manage,” “managing”, and “management”encompass preventing the recurrence of the specified disease or disorderin a patient who has already suffered from the disease or disorder,and/or lengthening the time that a patient who has suffered from thedisease or disorder remains in remission. The terms encompass modulatingthe threshold, development and/or duration of the disease or disorder,or changing the way that a patient responds to the disease or disorder.

The term “treating” refers to: (i) preventing a disease, disorder orcondition from occurring in a patient that may be predisposed to thedisease, disorder, and/or condition but has not yet been diagnosed ashaving it; (ii) inhibiting the disease, disorder, or condition, i.e.,arresting its development; and (iii) relieving the disease, disorder, orcondition, i.e., causing regression of the disease, disorder, and/orcondition.

This disclosure is intended to encompass compounds having Formula (I)when prepared by synthetic processes or by metabolic processes includingthose occurring in the human or animal body (in vivo) or processesoccurring in vitro.

EXAMPLES

The present disclosure will now be described in connection with certainembodiments which are not intended to limit its scope. On the contrary,the present disclosure covers all alternatives, modifications, andequivalents as can be included within the scope of the claims. Thus, thefollowing examples, which include specific embodiments, will illustrateone practice of the present disclosure, it being understood that theexamples are for the purposes of illustration of certain embodiments andare presented to provide what is believed to be the most useful andreadily understood description of its procedures and conceptual aspects.

The abbreviations used in the present application, includingparticularly in the illustrative schemes and examples which follow, arewell-known to those skilled in the art. Some of the abbreviations usedare as follows: MeOH for methanol; min for minutes, EtOAc or ETOAC forethyl acetate; h or hr or hrs for hours; Ph₃P for triphenylphosphine,DIAD for diisopropyl azodicarboxylate; RT or rt or r.t. for roomtemperature or retention time (context will dictate); t_(R) forretention time; EtOH for ethanol; DMSO for dimethylsulfoxide; THE fortetrahydrofuran; dppf for diphenylphosphinoferrocene; TFA fortrifluoracetic acid; NMP for N-methylpyrrolidine; CBz or Cbz forbenzyloxycarbonyl; DCM for dichloromethane; IPA for isopropyl alcohol;DMAP for N,N-dimethylaminopyridine; BOC or Boc for tert-butoxycarbonyl;(BOC)₂O for di-tert-butyl dicarbonate/DMF for N,N-dimethylformamide; OAcfor acetate; Cbz for carbobenzyloxy; TMS for trimethylsilane; LDA forlithium diisopropylamide; MOM-Cl for chloromethyl methyl ether; KHMDSfor potassium hexamethyldisilazide; KOtBu for potassium tert-butoxide;DAST for diethylaminosulfur trifloride; BuOH for n-butanol; n-BuLi forn-butyllithium; and NBS for N-bromosuccinimide.

The compounds of the present disclosure may be prepared using thereactions and techniques described in this section as well as othersynthetic methods known to those of ordinary skill in the art. Thereactions are performed in solvents appropriate to the reagents andmaterials employed and suitable for the transformation being affected.Also, in the description of the synthetic methods described below, it isto be understood that all proposed reaction conditions, including choiceof solvents, reaction temperature, duration of the experiment and workupprocedures, are chosen to be the conditions standard for that reaction,which should be readily recognized by one skilled in the art. It isunderstood by one skilled in the art of organic synthesis that thefunctionality present on various portions of the molecule must becompatible with the reagents and reactions proposed. Such restrictionsto the substituents which are compatible with the reaction conditionswill be readily apparent to one skilled in the art and alternate methodsmust then be used.

Compounds of Formula Ia can be synthesized following General Scheme I.The two key reactions, Suzuki coupling and ether formation, couldalternate as shown depending on the commercially available startingmaterials. The Suzuki coupling substrates, boronic acids/boronates, wereeither commercially available or prepared from corresponding halogenintermediates (Cl/Br/I) with various standard literature conditions. Theether formation can be achieved by SN_(AR) when a fluorine intermediate(Formula IV) is available, by Mitsunobu reaction or alkylation withsuitable amino alcohol when an OH is available (Formula III/V), and byBuchwald's Pd-catalyzed ether formation reaction when a Cl intermediate(Formula III/V) is available. In cases where R⁵ is bigger than H, anactivated form of the amino alcohol (Formula VII) was used as theOH-alkylating reagent. Sometimes N H₂ and OH were protected anddeprotected during the reaction sequence.

In the following examples, proton NMR spectra were recorded on either aBruker 400 or 500 MHz NMR spectrometer. Chemical shifts are reported in6 values relative to tetramethylsilane. Liquid chromatography (LC)/massspectra were run on a Shimadzu LC coupled to a Waters Micromass ZQ usingat least one of the following methods.

LC/MS Method A:

Column: Phenomenex LUNA C18, 30×2, 3 μm; Solvent A=5% MeOH: 95%

Water: 10 mM Ammonium Acetate; Solvent B=95% MeOH: 5% Water: 10 mM

Ammonium Acetate; Flow rate: 1 ml/min; Starting B=0%; Final B=100%;Gradient time=2 min; Run time: 3 min.

LC/MS Method B:

Column: Phenomenex LUNA C18, 30×2, 3 μm; Solvent A=10% MeOH: 90%

Water: 0.1% TFA; Solvent B=90% MeOH: 10% Water: 0.1% TFA; Flow rate: 1ml/min; Starting B=0%; Final B=100%; Gradient time=2 min; Run time: 3min.

LC/MS Method C:

Column: Phenomenex LUNA C18, 30×2, 3 μm; Solvent A=5% MeOH: 95%

Water: 10 mM Ammonium Acetate; Solvent B=95% MeOH: 5% Water: 10 mM

Ammonium Acetate; Flow rate: 0.8 ml/min; Starting B=0%; Final B=100%;Gradient time=4 min; Run time: 5 min.

Example 1(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)acetamide

Part A: N-(4-bromopyridin-2-yl)acetamide

To a mixture of 4-bromopyridin-2-amine (3.11 g, 17.98 mmol) in CH₂Cl₂(60 mL) at 0° C. was added acetyl chloride (1.406 mL, 19.77 mmol) andpyridine (1.745 mL, 21.57 mmol). The mixture was warmed to rt andstirred for 2 h. The reaction was quenched with water and diluted withEtOAc. The layers were separated. The organic layer was washed withwater, brine, dried (Na₂SO₄) and concentrated under reduced pressure toobtain N-(4-bromopyridin-2-yl)acetamide (3.82 g, 17.05 mmol, 95% yield)as a white solid. The material was carried on without furtherpurification. LCMS (ESI) m/e 215.0 [(M+H)⁺, calcd C₇H₈Br₁N₂O₁, 215.0];LC/MS retention time (method A): t_(R)=2.61 min.

Part B: N-(4-(3-fluoro-4-hydroxyphenyl)pyridin-2-yl)acetamide

To a 15 mL vial was added N-(4-bromopyridin-2-yl)acetamide (205.8 mg,0.957 mmol), (3-fluoro-4-hydroxyphenyl)boronic acid (239 mg, 1.531mmol), and Na₂CO₃ (1.435 mL, 2.87 mmol) in dioxane (3 mL) under nitrogento give a colorless solution.1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, toluene(39.4 mg, 0.048 mmol) was added under nitrogen. The vial was sealed andheated at 130° C. (microwave) for 2 h. The mixture was partitionedbetween water and EtOAc. The layers were separated. The organic layerwas washed with brine, dried (Na₂SO₄) and concentrated under reducedpressure to obtain N-(4-(3-fluoro-4-hydroxyphenyl)pyridin-2-yl)acetamide(200 mg, 0.812 mmol, 85% yield) as a tan solid. LCMS (ESI) m/e 247.0[(M+H)⁺, calcd C₁₃H₁₂F₁N₂O₂, 247.1]; LC/MS retention time (method A):t_(R)=1.51 min.

Part C: (S)-2-(I-hydroxy-4-methylpentan-2-yl)isoindoline-1,3-dione

To a 250 mL round-bottomed flask was added(S)-3-amino-5-methylhexan-1-ol (2.166 g, 16.51 mmol) andisobenzofuran-1,3-dione (2.445 g, 16.51 mmol) in toluene (60 mL) to givea colorless suspension. The mixture was heated at 110° C. for 16 h. Thevolatiles were removed under high vacuum to afford(S)-2-(1-hydroxy-4-methylpentan-2-yl)isoindoline-1,3-dione (4.08 g,16.51 mmol, quantitative yield) as a light yellow dense oil. LCMS (ESI)m/e 246.2 [(M−H)⁺, calcd C₁₄H₁₆N₁O₃, 246.1]; LC/MS retention time(method A): t_(R)=1.88 min.

Part D:(S)—N-(4-(4-((2-(1,3-dioxoisoindolin-2-yl)-4-methylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)acetamide

To a 50 mL round-bottomed flask was added(S)-2-(1-hydroxy-4-methylpentan-2-yl)isoindoline-1,3-dione (93 mg, 0.375mmol), Ph₃P (123 mg, 0.468 mmol), and(S)-2-(1-hydroxy-4-methylpentan-2-yl)isoindoline-1,3-dione (93 mg, 0.375mmol) in tetrahydrofuran (1 mL) to give a tan suspension. DIAD (0.091mL, 0.468 mmol) was added dropwise at rt. The resultant clear tansolution was stirred at rt for 19 h. The solution was concentrated underreduced pressure to give a tan oil which was carried directly into thenext reaction. LCMS (ESI) m/e 476.3 [(M+H)⁺, calcd C₂₇H₂₇F₁N₃O₄, 476.2];LC/MS retention time (method A): t_(R)=2.21 min.

Part E:(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)acetamide

To a 50 mL round-bottomed flask was added(S)—N-(4-(4-((2-(1,3-dioxoisoindolin-2-yl)-4-methylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)acetamide(148 mg, 0.312 mmol) in EtOH (2 mL) to give a tan solution. Hydrazine(0.049 mL, 1.560 mmol) was added and the mixture was heated at 60° C.for 2 h. The solution was cooled to rt and was concentrated underreduced pressure. The residue was suspended in MeOH, filtered, andpurified by prep-HPLC (24 mg, 0.069 mmol, 22% yield for 3 steps): ¹H NMR(500 MHz, DMSO-d₆) δ 10.53 (s, 1H), 8.33 (d, J=4.9 Hz, 2H), 7.61 (dd,J=12.5, 2.2 Hz, 1H), 7.52 (dd, J=8.5, 2.2 Hz, 1H), 7.43-7.37 (m, 1H),7.32 (t, J=8.7 Hz, 1H), 3.97 (dd, J=9.5, 4.9 Hz, 1H), 3.90 (dd, J=9.5,6.5 Hz, 1H), 3.12 (dt, J=11.9, 5.4 Hz, 1H), 2.12 (s, 3H), 1.81 (dq,J=13.0, 6.5 Hz, 1H), 1.33 (ddd, J=13.5, 8.5, 5.0 Hz, 1H), 1.26 (ddd,J=13.5, 8.5, 5.5 Hz, 1H), 0.92 (d, J=6.6 Hz, 3H), 0.88 (d, J=6.5 Hz,3H); LCMS (ESI) m/e 346.2 [(M+H)⁺, calcd C₁₉H₂₅F₁N₃O₂, 346.2]; LC/MSretention time (method A): t_(R)=1.89 min.

Alternative Synthesis of Example 1(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)acetamide

Part 2A: (S)-tert-butyl(1-(4-bromo-2-fluorophenoxy)-4-methylpentan-2-yl)carbamate

To a 15 mL vial was added (S)-tert-butyl(1-hydroxy-4-methylpentan-2-yl)carbamate (172 mg, 0.792 mmol), Ph₃P (260mg, 0.990 mmol), and 4-bromo-2-fluorophenol (126 mg, 0.660 mmol) intetrahydrofuran (2 mL) to give a tan solution. DIAD (0.180 mL, 0.924mmol) was added at rt. The resulted clear tan solution was stirred at rtfor 16 h. The solution was concentrated under reduced pressure to afforda tan oil which was directly purified by silica gel columnchromatography (up to 60% EtOAc/hexane to afford (S)-tert-butyl(1-(4-bromo-2-fluorophenoxy)-4-methylpentan-2-yl)carbamate (249 mg,0.638 mmol, 97% yield) as a colorless oil: ¹H NMR (400 MHz,Chloroform-d) δ 7.24 (dd, J=10.5, 2.4 Hz, 1H), 7.21-7.16 (m, 1H),6.90-6.81 (m, 1H), 4.83-4.69 (m, 1H), 4.08-3.92 (m, 3H), 1.71 (dp,J=13.2, 6.6 Hz, 1H), 1.59-1.49 (m, 2H), 1.47 (d, J=3.8 Hz, 9H), 0.96(dd, J=6.6, 4.4 Hz, 6H); LCMS (ESI) m/e 412.1 [(M+Na)⁺, calcdC₁₇H₂₅BrFNNaO₃, 412.1]; LC/MS retention time (method B): t_(R)=2.41 min.

Part 2B: (S)-tert-butyl(1-(4-(2-acetamidopyridin-4-yl)-2-fluorophenoxy)-4-methylpentan-2-yl)carbamate

To a 15 mL vial was addedN-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide(208 mg, 0.792 mmol), (S)-tert-butyl(1-(4-bromo-2-fluorophenoxy)-4-methylpentan-2-yl)carbamate (258 mg, 0.66mmol), and Na₂CO₃ (0.990 mL, 1.980 mmol) in dioxane (2 mL) undernitrogen to give a colorless suspension.1,1′-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride, toluene(27.1 mg, 0.033 mmol) was added under nitrogen. The vial was sealed andheated at 130° C. (microwave) for 2 h. The mixture was diluted withwater and EtOAc. The layers were separated. The organic layer was washedwith brine, dried (Na₂SO₄) and concentrated. The residue was purified bysilica gel column chromatography (up to 70% EtOAc/hexane) to afford thedesired product (200 mg, 0.449 mmol, 68% yield for two steps) as acolorless oil: ¹H NMR (400 MHz, Chloroform-d) δ 8.79 (s, 1H), 8.46 (s,1H), 8.29 (d, J=5.4 Hz, 1H), 7.50-7.38 (m, 2H), 7.21 (dd, J=5.2, 1.7 Hz,1H), 7.06 (t, J=8.7 Hz, 1H), 4.81 (d, J=9.2 Hz, 1H), 4.12-3.96 (m, 3H),2.25 (s, 3H), 1.74 (dq, J=13.5, 6.5, 6.1 Hz, 1H), 1.63-1.52 (m, 2H),1.47 (s, 9H), 0.98 (dd, J=6.6, 3.3 Hz, 6H); LCMS (ESI) m/e 446.2[(M+H)⁻, calcd C₂₄H₃₃F₁N₃O₄, 446.2]; LC/MS retention time (method B):t_(R)=2.11 min.

Part 2C:(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)acetamide

To a 50 mL round-bottomed flask was added (S)-tert-butyl(1-(4-(2-acetamidopyridin-4-yl)-2-fluorophenoxy)-4-methylpentan-2-yl)carbamate(202 mg, 0.453 mmol) in dichloromethane (2 mL) to give a colorlesssolution. TFA (0.5 mL) was added, and the resulted tan solution wasstirred at rt for 1 h. The volatiles were removed under reducedpressure. The residue was diluted with EtOAc and basified with 1N NaOH.The layers were separated. The organic layer was washed with brine,dried (Na₂SO₄) and concentrated under reduced pressure to afford(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)acetamide(155 mg, 0.449 mmol, 99% yield) as a slightly tan oil: ¹H NMR and LCMSmatched that of the previously prepared; ¹⁹F NMR (376 MHz, Chloroform-d)δ −133.47.

Example 2(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-methoxyphenyl)pyridin-2-yl)acetamide

Prepared as described in Example 1.

Part A: N-(4-(3-methoxy-4-hydroxyphenyl)pyridin-2-yl)acetamide

LCMS (ESI) m/e 259.1 [(M+H)⁺, calcd C₁₄H₁₅N₂O₃, 259.3]; LC/MS retentiontime (method A): t_(R)=1.51 min.

Part B:(S)—N-(4-(4-((2-(1,3-dioxoisoindolin-2-yl)-4-methylpentyl)oxy)-3-methoxyphenyl)pyridin-2-yl)acetamide

LCMS (ESI) m/e 488.3 [(M+H)⁺, calcd C₂H₃₀N₃O₅, 488.2]; LC/MS retentiontime (method A): t_(R)=2.17 min.

Part C:(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-methoxyphenyl)pyridin-2-yl)acetamide

Obtained(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-methoxyphenyl)pyridin-2-yl)acetamide(14.9 mg, 0.042 mmol, 80% yield for final step) as a slightly tan foam:¹H NMR (500 MHz, DMSO-d₆) δ 10.50 (s, 1H), 8.35 (s, 1H), 8.32 (d, J=5.2Hz, 1H), 7.40 (dd, J=5.2, 1.8 Hz, 1H), 7.32-7.22 (m, 2H), 7.12 (d, J=8.2Hz, 1H), 3.90 (dd, J=9.3, 4.6 Hz, 1H), 3.87 (s, 3H), 3.78 (dd, J=9.4,6.9 Hz, 1H), 3.09 (p, J=5.5, 5.1 Hz, 1H), 2.12 (s, 3H), 1.82 (dt,J=13.4, 6.7 Hz, 1H), 1.32 (ddd, J=13.5, 8.6, 5.0 Hz, 1H), 1.24 (ddd,J=13.6, 8.7, 5.5 Hz, 1H), 0.92 (d, J=6.6 Hz, 3H), 0.89 (d, J=6.5 Hz,3H); LCMS (ESI) m/e 358.2 [(M+H)⁺, calcd C₂₀H₂₈N₃O₃, 358.2]; LC/MSretention time (method A): t_(R)=1.70 min.

Example 3(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide

Prepared as described in Example 1.

Part A:(S)-5-bromo-2-((2-(1,3-dioxoisoindolin-2-yl)-4-methylpentyl)oxy)benzonitrile

¹H NMR (400 MHz, Chloroform-d) δ 7.86 (dd, J=5.4, 3.0 Hz, 2H), 7.74 (dd,J=5.5, 3.1 Hz, 2H), 7.63-7.55 (m, 2H), 6.87 (d, J=8.8 Hz, 1H), 4.85(tdd, J=9.8, 5.6, 3.9 Hz, 1H), 4.57 (t, J=9.2 Hz, 1H), 4.32 (dd, J=9.3,5.7 Hz, 1H), 2.28-2.14 (m, 1H), 1.66-1.53 (m, 2H), 1.00 (d, J=5.8 Hz,3H), 0.96 (d, J=6.0 Hz, 3H); LCMS (ESI) m/e 427.1 [(M+H)⁺, calcdC₂₁H₂Br₁N₂O₃, 427.1]; LC/MS retention time (method B): t_(R)=2.29 min.

Part B:(S)—N-(4-(3-cyano-4-((2-(1,3-dioxoisoindolin-2-yl)-4-methylpentyl)oxy)phenyl)pyridin-2-yl)acetamide

LCMS (ESI) m/e 483.3 [(M+H)⁺, calcd C₂₈H₂₇N₄O₄, 483.2]; LC/MS retentiontime (method B): t_(R)=2.06 min.

Part C:(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide

Acetamide was partially hydrolyzed (see Example 4) and the two productswere separated and identified. Obtained(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide(10.1 mg, 0.028 mmol, 23% yield) as a colorless foam. ¹H NMR (500 MHz,DMSO-d₆) δ 10.58 (s, 1H), 8.39-8.32 (m, 2H), 8.12 (d, J=2.5 Hz, 1H),8.00 (dd, J=8.8, 2.5 Hz, 1H), 7.44 (d, J=5.4 Hz, 1H), 7.41 (d, J=8.8 Hz,1H), 4.05 (dd, J=9.3, 5.0 Hz, 1H), 3.99 (t, J=7.9 Hz, 1H), 3.12 (s, 1H),2.13 (s, 3H), 1.84 (p, J=6.6 Hz, 1H), 1.42-1.31 (m, 1H), 1.27 (dq,J=14.0, 7.0, 6.2 Hz, 1H), 0.93 (d, J=6.6 Hz, 3H), 0.89 (d, J=6.4 Hz,3H); LCMS (ESI) m/e 353.2 [(M+H)⁺, calcd C₂H₂₅N₄O₂, 353.2]; LC/MSretention time (method B): t_(R)=1.44 min.

Example 4(S)-2-((2-amino-4-methylpentyl)oxy)-5-(2-aminopyridin-4-yl)benzonitrile

The hydrolyzed material from Example 3 was identified as(S)-2-((2-amino-4-methylpentyl)oxy)-5-(2-aminopyridin-4-yl)benzonitrile(10.1 mg, 0.030 mmol, 26% yield) as a colorless foam. ¹H NMR (500 MHz,DMSO-d₆) δ 8.02 (d, J=2.4 Hz, 1H), 7.97 (d, J=5.3 Hz, 1H), 7.93 (dd,J=8.8, 2.4 Hz, 1H), 7.36 (d, J=8.9 Hz, 1H), 6.82 (dd, J=5.3, 1.6 Hz,1H), 6.70 (s, 1H), 5.97 (s, 2H), 4.03 (dd, J=9.3, 5.1 Hz, 1H), 3.96 (t,J=7.7 Hz, 1H), 3.10 (s, 1H), 1.84 (p, J=6.4 Hz, 1H), 1.35 (q, J=9.3, 6.6Hz, 1H), 1.26 (dq, J=13.7, 6.8, 6.1 Hz, 1H), 0.92 (d, J=6.6 Hz, 3H),0.89 (d, J=6.5 Hz, 3H); LCMS (ESI) m/e 311.2 [(M+H)⁺, calcd C₁₈H₂₃N₄O₁,311.2]; LC/MS retention time (method B): t_(R)=1.35 min.

Example 5(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide

Prepared as described in Example 1.

Part A: (S)-tert-butyl(1-(4-bromo-2-(trifluoromethyl)phenoxy)-4-methylpentan-2-yl)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 7.67 (d, J=2.4 Hz, 1H), 7.57 (dd,J=8.8, 2.5 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 4.71 (d, J=8.3 Hz, 1H), 4.03(p, J=7.2 Hz, 3H), 1.68 (hept, J=6.7 Hz, 1H), 1.55-1.48 (m, 2H), 1.44(s, 9H), 0.95 (dd, J=6.6, 4.2 Hz, 6H); LCMS (ESI) m/e 462.1 [(M+Na)⁺,calcd C₁₈H₂₅Br₁F₃N₁Na₁O₃, 462.1]; LC/MS retention time (method B):t_(R)=2.45 min.

Part B: (S)-tert-butyl(1-(4-(2-acetamidopyridin-4-yl)-2-(trifluoromethyl)phenoxy)-4-methylpentan-2-yl)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 9.50 (s, 1H), 8.48 (s, 1H), 8.29 (d,J=5.3 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.81 (dd, J=8.5, 2.4 Hz, 1H),7.21 (dd, J=5.3, 1.7 Hz, 1H), 7.08 (d, J=8.6 Hz, 1H), 4.79 (d, J=8.7 Hz,1H), 4.13-4.04 (m, 3H), 2.25 (s, 3H), 1.70 (dt, J=13.6, 6.9 Hz, 1H),1.54 (t, J=7.2 Hz, 2H), 1.44 (s, 9H), 0.96 (d, J=2.8 Hz, 3H), 0.95 (d,J=2.7 Hz, 3H); LCMS (ESI) m/e 496.2 [(M+H)⁺, calcd C₂₅H₃₃F₃N₃O₄, 446.2];LC/MS retention time (method A): t_(R)=2.28 min.

Part C:(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide

(221 mg, 0.531 mmol, quantitative yield for final step) as a white foam.¹H NMR (400 MHz, Chloroform-d) δ 9.15 (s, 1H), 8.48 (s, 1H), 8.30 (d,J=5.3 Hz, 1H), 7.88 (d, J=2.2 Hz, 1H), 7.82 (dd, J=8.7, 2.3 Hz, 1H),7.23 (dd, J=5.3, 1.7 Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 4.08 (dd, J=8.7,3.6 Hz, 1H), 3.85 (dd, J=8.7, 7.1 Hz, 1H), 3.32 (qd, J=7.0, 3.6 Hz, 1H),2.25 (s, 3H), 1.80 (dp, J=13.5, 6.7 Hz, 1H), 1.57 (s, 2H), 1.38 (t,J=7.0 Hz, 2H), 0.98 (d, J=6.5 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H); ¹⁹F NMR(376 MHz, Chloroform-d) δ −62.40; LCMS (ESI) m/e 394.2 [(M−H), calcdC₂₀H₂₃F₃N₃O₂, 394.2]; LC/MS retention time (method A): t_(R)=1.97 min.

Example 6(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamide

Prepared as described in Example 1.

Part A: (S)-tert-butyl(1-(4-bromo-2-(trifluoromethoxy)phenoxy)-4-methylpentan-2-yl)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 7.42-7.33 (m, 2H), 6.89 (d, J=8.8 Hz,1H), 4.78-4.61 (m, 1H), 4.09-3.90 (m, 3H), 1.68 (dq, J=13.3, 6.7 Hz,1H), 1.51 (t, J=6.8 Hz, 2H), 1.45 (s, 9H), 0.95 (dd, J=6.6, 5.4 Hz, 6H);LCMS (ESI) m/e 478.1 [(M+Na)⁺, calcd C₁₈H₂₅Br₁F₃N₁Na₁O₄, 478.0]; LC/MSretention time (method B): t_(R)=2.45 min.

Part B: (S)-tert-butyl(1-(4-(2-acetamidopyridin-4-yl)-2-(trifluoromethoxy)phenoxy)-4-methylpentan-2-yl)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 9.13 (s, 1H), 8.47 (s, 1H), 8.29 (d,J=5.3 Hz, 1H), 7.61 (dd, J=8.5, 2.3 Hz, 1H), 7.56 (q, J=1.3 Hz, 1H),7.21 (dd, J=5.3, 1.7 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 4.77 (d, J=8.3 Hz,1H), 4.12-3.98 (m, 3H), 2.25 (s, 3H), 1.73 (dq, J=13.7, 7.1, 6.4 Hz,1H), 1.55 (t, J=7.0 Hz, 2H), 1.46 (s, 9H), 0.97 (dd, J=6.6, 4.1 Hz, 6H);LCMS (ESI) m/e 512.2 [(M+H)⁺, calcd C₂₅H₃₃F₃N₃O₅, 512.2]; LC/MSretention time (method A): t_(R)=2.29 min.

Part C:(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamide

(225 mg, 0.520 mmol, 95% yield for final step) as a white foam. ¹H NMR(400 MHz, Chloroform-d) δ 9.59 (s, 1H), 8.47 (s, 1H), 8.27 (d, J=5.3 Hz,1H), 7.58 (dd, J=8.5, 2.3 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.19 (dd,J=5.4, 1.7 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 4.00 (dd, J=8.8, 3.7 Hz,1H), 3.80 (dd, J=8.8, 7.3 Hz, 1H), 3.31 (qd, J=7.1, 3.7 Hz, 1H), 2.23(s, 3H), 1.86-1.72 (m, J=6.9 Hz, 1H), 1.63 (s, 2H), 1.35 (t, J=7.0 Hz,2H), 0.95 (dd, J=9.1, 6.6 Hz, 6H); ¹⁹F NMR (376 MHz, Chloroform-d) δ−58.10; LCMS (ESI) m/e 412.1 [(M+H)⁺, calcd C₂₀H₂₅F₃N₃O₃, 412.2]; LC/MSretention time (method A): t_(R)=1.99 min.

Example 7(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-methylphenyl)pyridin-2-yl)acetamide

Part A:(S)-tert-butyl(1-(4-bromo-2-methylphenoxy)-4-methylpentan-2-yl)carbamate

DIAD (0.090 mL, 0.464 mmol) was added to a solution oftriphenylphosphine(0.097 g, 0.371 mmol), 4-bromo-2-methylphenol (0.069g, 0.371 mmol) and (S)-tert-butyl(1-hydroxy-4-methylpentan-2-yl)carbamate (0.0672 g, 0.309 mmol) in THE(1.5 mL) at rt under N₂. The reaction was stirred at room temperatureovernight. The solvent was removed under reduced pressure. The residuewas purified via silica gel chromatography (0 to 25% ethyl acetate inhexanes). NMR and LCMS showed the product contained the startingmaterial (4-bromo-2-methoxyphenol). This mixture was taken up in ethylacetate and washed with 1N NaOH (2×) and water (1×). The ethyl acetatelayer was separated, dried (Na2SO4), filtered and concentrated underreduced pressure to give (S)-tert-butyl(1-(4-bromo-2-methylphenoxy)-4-methylpentan-2-yl)carbamate (31.2 mg,0.081 mmol, 26% yield) as a colorless wax. LCMS (ESI) m/e 408.1[(M+Na)⁺, calcd C₁₈H₂₈BrNO₃Na, 408.1]; LC/MS retention time (method B):t_(R)=2.44 min.

Part B: (S)-tert-butyl(1-(4-(2-acetamidopyridin-4-yl)-2-methylphenoxy)-4-methylpentan-2-yl)carbamate

A mixture of sodium carbonate (0.061 mL, 0.121 mmol),N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide(0.028 g, 0.105 mmol), (S)-tert-butyl(1-(4-bromo-2-methylphenoxy)-4-methylpentan-2-yl)carbamate (0.0312 g,0.081 mmol) in dioxane (1 mL) was purged with nitrogen 5 times.PdCl₂(dppf) (5.91 mg, 8.08 μmol) was added to the reaction mixture andthe reaction was heated at 80° C. overnight. The reaction was cooled toroom temperature and diluted with ethyl acetate. The organic layer wasseparated and washed with brine (1×). The ethyl acetate layer wasseparated, dried (Na₂SO₄), filtered and concentrated under reducedpressure. The crude was used as it is at the next reaction. LCMS (ESI)m/e 442.3 [(M+H)⁺, calcd C₂₅H₃₆N₃O₄, 442.3]; LC/MS retention time(method B): t_(R)=2.13 min.

Part C:(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-methylphenyl)pyridin-2-yl)acetamide

A mixture of TFA (1 mL, 12.98 mmol) and (S)-tert-butyl(1-(4-(2-acetamidopyridin-4-yl)-2-methylphenoxy)-4-methylpentan-2-yl)carbamate(35.8 mg, 0.081 mmol) in CH₂Cl₂ (4 mL) was stirred at room temperaturefor 1 h. The solvent was removed under reduced pressure and the residuewas purified via reverse phase HPLC (acetonitrile/water/10 mM ammoniumacetate). To afford(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-methylphenyl)pyridin-2-yl)acetamide(9.7 mg, 0.028 mmol, 35% yield for two steps). ¹H NMR (500 MHz, DMSO-d₆)δ 10.50 (s, 1H), 8.34 (br. s., 1H), 8.30 (d, J=5.2 Hz, 1H), 7.53 (br.s., 2H), 7.35 (d, J=4.6 Hz, 1H), 7.08-7.03 (m, J=9.2 Hz, 1H), 3.92-3.86(m, 1H), 3.84-3.78 (m, 1H), 3.10 (br. s., 1H), 2.26 (s, 3H), 2.12 (s,3H), 1.87-1.79 (m, 1H), 1.40-1.31 (m, 1H), 1.27 (d, J=6.4 Hz, 1H), 0.93(d, J=6.7 Hz, 3H), 0.89 (d, J=6.4 Hz, 3H); LCMS (ESI) m/e 342.2 [(M+H)⁺,calcd C₂₀H₂₈N₃O₂, 342.2]; LC/MS retention time (method B): t_(R)=1.73min.

Example 8(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-chlorophenyl)pyridin-2-yl)acetamide

Part A: (S)-tert-butyl(1-(4-bromo-2-chlorophenoxy)-4-methylpentan-2-yl)carbamate

Prepared as described in Example 1, Part 2A. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.52 (d, J=2.5 Hz, 1H), 7.33 (dd, J=8.8, 2.5 Hz, 1H),6.82 (d, J=8.8 Hz, 1H), 4.08-3.95 (m, 3H), 1.77-1.66 (m, 1H), 1.57 (br.m, 2H), 1.47 (s, 9H), 0.98 (dd, J=6.5, 3.8 Hz, 6H). LCMS (ESI) m/e 428.0[(M+Na)⁺, calcd C₁₇H₂₅BrClNO₃Na, 428.1]; LC/MS retention time (methodB): t_(R)=2.47 min.

Part B: (S)-tert-butyl(1-(4-(2-acetamidopyridin-4-yl)-2-chlorophenoxy)-4-methylpentan-2-yl)carbamate

The mixture of sodium carbonate (0.113 mL, 0.226 mmol),N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide(0.051 g, 0.196 mmol), (S)-tert-butyl(1-(4-bromo-2-chlorophenoxy)-4-methylpentan-2-yl)carbamate (0.0612 g,0.150 mmol) in dioxane (1 mL) was evacuated and back-filled with N₂(5×). PdCl₂(dppf) (0.011 g, 0.015 mmol) was added to the reactionmixture and the reaction was heated at 80° C. overnight. The reactionwas diluted with ethyl acetate and washed with brine (1×). The ethylacetate layer was separated, dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The crude was purified by silica gelchromatography (50% ethyl acetate in hexanes) to afford. (S)-tert-butyl(1-(4-(2-acetamidopyridin-4-yl)-2-chlorophenoxy)-4-methylpentan-2-yl)carbamate(51.7 mg, 0.112 mmol, 74% yield). LCMS (ESI) m/e 462.2 [(M+H)⁺, calcdC₂₄H₃₃ClN₃O₄, 462.2]; LC/MS retention time (method B): t_(R)=2.21 min.

Part C:(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-chlorophenyl)pyridin-2-yl)acetamide

A mixture of (S)-tert-butyl(1-(4-(2-acetamidopyridin-4-yl)-2-chlorophenoxy)-4-methylpentan-2-yl)carbamate(51.7 mg, 0.112 mmol) and TFA (1 mL, 12.98 mmol) was stirred in CH₂Cl₂(3 mL) at room temperature for 2 h. The solvent was removed underreduced pressure and the residue was purified via reverse phase HPLC(acetonitrile/water/10 mM ammonium acetate). (42.7 mg, 0.111 mmol, 99%yield). ¹H NMR (500 MHz, DMSO-d₆) δ 10.58 (br. s., 1H), 8.35 (d, J=4.6Hz, 2H), 7.81 (s, 1H), 7.70 (d, J=8.9 Hz, 1H), 7.42 (d, J=5.2 Hz, 1H),7.33 (d, J=8.5 Hz, 1H), 4.18-4.12 (m, 1H), 4.08-4.01 (m, 1H), 3.39-3.35(m, 1H), 2.13 (s, 3H), 1.86-1.74 (m, 1H), 1.50 (d, J=6.1 Hz, 1H),1.45-1.36 (m, 1H), 0.92 (dd, J=10.2, 6.6 Hz, 6H); LCMS (ESI) m/e 362.2[(M+H)⁺, calcd C₁₉H₂₅ClN₃O₃, 362.2]; LC/MS retention time (method B):t_(R)=1.69 min.

Example 9(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3,5-difluorophenyl)pyridin-2-yl)acetamide

Prepared as described in Example 1.

Part A: (S)-tert-butyl(1-(4-bromo-2,6-difluorophenoxy)-4-methylpentan-2-yl)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 7.42-7.33 (m, 2H), 6.89 (d, J=8.8 Hz,1H), 4.78-4.61 (m, 1H), 4.09-3.90 (m, 3H), 1.68 (dq, J=13.3, 6.7 Hz,1H), 1.51 (t, J=6.8 Hz, 2H), 1.45 (s, 9H), 0.95 (dd, J=6.6, 5.4 Hz, 6H);LCMS (ESI) m/e 478.1 [(M+Na)⁺, calcd C₁₈H₂₅Br₁F₃N₁Na₁O₄, 478.0]; LC/MSretention time (method B): t_(R)=2.45 min.

Part B: (S)-tert-butyl(1-(4-(2-acetamidopyridin-4-yl)-2,6-difluorophenoxy)-4-methylpentan-2-yl)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 9.01 (s, 1H), 8.42 (s, 1H), 8.28 (d,J=5.3 Hz, 1H), 7.22 (d, J=8.7 Hz, 2H), 7.15 (dd, J=5.4, 1.7 Hz, 1H),4.88 (d, J=9.0 Hz, 1H), 4.24-4.13 (m, 2H), 3.94 (s, 1H), 2.24 (s, 3H),1.74 (dt, J=13.5, 6.7 Hz, 1H), 1.55 (t, J=7.3 Hz, 2H), 1.24 (s, 9H),0.97 (d, J=6.5 Hz, 6H); ¹⁹F NMR (376 MHz, Chloroform-d) δ −126.89; LCMS(ESI) m/e 464.2 [(M+H)⁺, calcd C₂₄H₃₂F₂N₃O₄, 464.2]; LC/MS retentiontime (method A): t_(R)=2.24 min.

Part C:(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3,5-difluorophenyl)pyridin-2-yl)acetamide

Obtained(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3,5-difluorophenyl)pyridin-2-yl)acetamide(48.4 mg, 0.152 mmol, 99% yield for final step) as an off-white foam. ¹HNMR (500 MHz, DMSO-d₆) δ 10.62 (s, 1H), 8.37 (d, J=5.3 Hz, 1H), 8.32 (s,1H), 7.59-7.48 (m, 2H), 7.42 (dd, J=5.2, 1.8 Hz, 1H), 4.16 (dd, J=10.0,4.5 Hz, 1H), 4.07 (dd, J=9.9, 5.7 Hz, 1H), 3.24 (dq, J=10.5, 5.8 Hz,1H), 2.13 (s, 3H), 1.82-1.74 (m, 1H), 1.46 (ddd, J=13.7, 8.1, 5.8 Hz,1H), 1.35 (ddd, J=13.9, 8.1, 6.3 Hz, 1H), 0.90 (dd, J=9.0, 6.5 Hz, 6H);LCMS (ESI) m/e 364.1 [(M+H)⁺, calcd C₁₉H₂₄F₂N₃O₂, 364.2]; LC/MSretention time (method A): t_(R)=1.81 min.

Example 10(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-chloro-5-fluorophenyl)pyridin-2-yl)acetamide

Prepared as described in Example 1.

Part A: (S)-tert-butyl(1-(4-bromo-2,6-difluorophenoxy)-4-methylpentan-2-yl)carbamate

LCMS (ESI) m/e 424.2 [(M+H)⁺, calcd C₁₇H₂₅Br₁Cl₁F₁N₁O₃, 424.1]; LC/MSretention time (method A): t_(R)=2.37 min.

Part B (S)-tert-buty(1-(4-(2-acetamdopyridin-4-yl)-2-chloro-6-fluorophenoxy)-4-methylpentan-2-yl)carbamate

LCMS (ESI) m/e 480.2 [(M+H)⁺, calcd C₂₄H₃₂F₂N₃O₄, 480.2]; LC/MSretention time (method B): t_(R)=2.28 min.

Part C:(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-chloro-5-fluorophenyl)pyridin-2-yl)acetamide

Obtained(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-chloro-5-fluorophenyl)pyridin-2-yl)acetamide(26.5 mg, 0.066 mmol, 56% yield for final step) as a colorless solid. ¹HNMR (500 MHz, DMSO-d₆) δ 10.60 (s, 1H), 8.37 (d, J=5.2 Hz, 1H), 8.30 (s,1H), 7.67 (d, J=9.5 Hz, 2H), 7.43 (d, J=5.1 Hz, 1H), 4.04 (dd, J=9.4,4.7 Hz, 1H), 3.96 (dd, J=9.5, 6.2 Hz, 1H), 3.11 (dq, J=10.7, 5.1 Hz,1H), 2.12 (s, 3H), 1.79 (dq, J=13.6, 6.4 Hz, 1H), 1.41 (ddd, J=13.6,8.5, 5.2 Hz, 1H), 1.26 (ddd, J=14.1, 8.6, 5.8 Hz, 1H), 0.91 (d, J=6.5Hz, 3H), 0.88 (d, J=6.5 Hz, 3H); LCMS (ESI) m/e 380.2 [(M+H)⁺, calcdC₁₉H₂₄Cl₁F₁N₃O₂, 380.2]; LC/MS retention time (method B): t_(R)=1.82min.

Example 11(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluoro-5-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide

Prepared as described in Example 1.

Part A: (S)-tert-butyl(1-(4-bromo-2-fluoro-6-(trifluoromethyl)phenoxy)-4-methylpentan-2-yl)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 7.52 (t, J=1.9 Hz, 1H), 7.47 (dd,J=10.7, 2.4 Hz, 1H), 4.76 (d, J=9.1 Hz, 1H), 4.19 (s, 2H), 3.96 (d,J=7.7 Hz, 1H), 1.74 (dq, J=13.5, 6.7 Hz, 1H), 1.54 (t, J=7.1 Hz, 2H),1.47 (s, 9H), 0.98 (d, J=6.6 Hz, 6H); LCMS (ESI) m/e 480.0 [(M+Na)⁺,calcd C₁₈H₂₄Br₁F₄N₁Na₁O₃, 480.1]; LC/MS retention time (method B):t_(R)=2.50 min.

Part B: (S)-tert-butyl(1-(4-(2-acetamidopyridin-4-yl)-2-fluoro-6-(trifluoromethyl)phenoxy)-4-methylpentan-2-yl)carbamate

LCMS (ESI) m/e 536.2 [(M+Na)⁺, calcd C₂₅H₃₁F₄Na₁N₃O₄, 536.2]; LC/MSretention time (method B): t_(R)=2.34 min.

Part C:(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluoro-5-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide

Obtained(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluoro-5-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide(49 mg, 0.116 mmol, 75% yield for final step) as a colorless solid. ¹HNMR (500 MHz, DMSO-d₆) δ 10.63 (s, 1H), 8.39 (d, J=5.3 Hz, 1H), 8.35 (s,1H), 8.01 (dd, J=12.9, 2.2 Hz, 1H), 7.74 (s, 1H), 7.48 (d, J=5.4 Hz,1H), 4.06 (p, J=8.2 Hz, 2H), 3.12-3.03 (m, 1H), 2.13 (s, 3H), 1.82 (dt,J=13.6, 7.2 Hz, 1H), 1.35 (ddd, J=13.4, 8.9, 4.8 Hz, 1H), 1.22 (ddd,J=13.8, 9.0, 5.5 Hz, 1H), 0.92 (d, J=6.6 Hz, 3H), 0.88 (d, J=6.6 Hz,3H); LCMS (ESI) m/e 414.2 [(M+H)⁺, calcd C₂₀H₂₄F₄N₃O₂, 414.2]; LC/MSretention time (method A): t_(R)=2.01 min.

Example 12(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-2,5-difluorophenyl)pyridin-2-yl)acetamide

Prepared as described in Example 1.

Part A: (S)-tert-butyl(1-(4-bromo-2,5-difluorophenoxy)-4-methylpentan-2-yl)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 7.29 (t, J=9.5 Hz, 1H), 6.81 (dd,J=9.5, 7.3 Hz, 1H), 4.68 (s, 1H), 4.09-3.91 (m, 3H), 1.71 (dt, J=13.4,7.0 Hz, 1H), 1.53 (dd, J=15.3, 7.8 Hz, 2H), 1.47 (s, 9H), 0.97 (dd,J=6.6, 4.5 Hz, 6H); LCMS (ESI) m/e 408.0 [(M+H)⁺, calcd C₁₇H₂₅Br₁F₂N₁O₃,408.1]; LC/MS retention time (method A): t_(R)=2.40 min.

Part B: (S)-tert-butyl(1-(4-(2-acetamidopyridin-4-yl)-2,5-difluorophenoxy)-4-methylpentan-2-yl)carbamate

LCMS (ESI) m/e 464.2 [(M+H)⁺, calcd C₂₄H₃₂F₂N₃O₄, 464.3]; LC/MSretention time (method A): t_(R)=2.29 min.

Part C:(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-2,5-difluorophenyl)pyridin-2-yl)acetamide

Obtained(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-2,5-difluorophenyl)pyridin-2-yl)acetamide(46.4 mg, 0.125 mmol, 77% yield for final step) as a colorless solid. ¹HNMR (500 MHz, DMSO-d₆) δ 10.59 (s, 1H), 8.37 (d, J=5.2 Hz, 1H), 8.29 (s,1H), 7.54 (dd, J=11.8, 7.3 Hz, 1H), 7.34 (dd, J=12.3, 7.2 Hz, 1H), 7.26(d, J=5.2 Hz, 1H), 4.08 (dd, J=9.8, 4.5 Hz, 1H), 3.98 (dd, J=10.0, 6.4Hz, 1H), 3.24 (p, J=6.0 Hz, 1H), 2.11 (s, 3H), 1.80 (dq, J=15.3, 8.4,7.6 Hz, 1H), 1.35 (qt, J=13.7, 6.8 Hz, 2H), 0.91 (dd, J=14.1, 6.6 Hz,6H); LCMS (ESI) m/e 364.2 [(M+H)⁺, calcd C₁₉H₂₄F₂N₃O₂, 364.2]; LC/MSretention time (method A): t_(R)=1.82 min.

Example 13 (S)-methyl(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)carbamate

Prepared as described in Example 1.

Part A: (2-((methoxycarbonyl)amino)pyridin-4-yl)boronic acid

The mixture of2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl(0.079 g, 0.166mmol), potassium acetate(2.446 g, 24.92 mmol), 2^(nd) generation Xphosprecatalyst (0.065 g, 0.083 mmol), methyl(4-chloropyridin-2-yl)carbamate (1.55 g, 8.31 mmol) and hypodiboric acid(1.117 g, 12.46 mmol) in ethanol (80 mL) was degassed three times viavacuum/N₂ fill cycle. The reaction mixture was heated at 80° C. for 3 h.The reaction mixture was cooled to rt and the solvent was removed underreduced pressure and the solid was washed with acetone. The remainingsolid was suspended with mixture of methanol and CH₂Cl₂. The suspensionwas filtered and the filtrate was concentrated under reduced pressure togive the crude product as a solid. The solid was suspended in water andfiltered. The solid was washed with acetone to give(2-((methoxycarbonyl)amino)pyridin-4-yl)boronic acid (702 mg, 3.58 mmol,43% yield) as an off-white solid. LCMS (ESI) m/e 197.2 [(M+H)⁺, calcdC₇H₁₀BN₂O₄, 197.1]; LC/MS retention time (method B): t_(R)=0.46 min.

Part B: (S)-tert-butyl(1-(4-(2-aminopyridin-4-yl)-2-fluorophenoxy)-4-methylpentan-2-yl)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 9.86 (s, 1H), 8.35 (d, J=5.4 Hz, 1H),8.31-8.24 (m, 1H), 7.52-7.39 (m, 2H), 7.17 (dd, J=5.4, 1.7 Hz, 1H), 7.06(t, J=8.6 Hz, 1H), 4.84 (d, J=8.5 Hz, 1H), 4.15-3.99 (m, 3H), 3.87 (s,3H), 1.80-1.67 (m, 1H), 1.56 (dt, J=13.3, 7.8 Hz, 2H), 1.47 (s, 9H),0.99 (d, J=3.7 Hz, 3H), 0.97 (d, J=3.6 Hz, 3H); ¹⁹F NMR (376 MHz,Chloroform-d) δ −133.39; LCMS (ESI) m/e 462.2 [(M+H)⁺, calcdC₂₄H₃₃F₁N₃O₅, 462.2]; LC/MS retention time (method B): t_(R)=2.20 min.

Part C: (S)-methyl(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)carbamate

Obtained (S)-methyl(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)carbamate(33.2 mg, 0.091 mmol, 93% yield for the final step) as an off-whitesolid. ¹H NMR (500 MHz, DMSO-d₆) δ 10.26 (s, 1H), 8.30 (d, J=5.3 Hz,1H), 8.09 (s, 1H), 7.63 (dd, J=12.7, 2.4 Hz, 1H), 7.55-7.49 (m, 1H),7.37 (dd, J=5.3, 1.9 Hz, 1H), 7.32 (t, J=8.7 Hz, 1H), 3.97 (dd, J=9.4,5.0 Hz, 1H), 3.90 (dd, J=9.4, 6.5 Hz, 1H), 3.71 (s, 3H), 3.12 (p, J=5.6Hz, 1H), 1.83 (dt, J=14.1, 6.7 Hz, 1H), 1.33 (ddd, J=13.4, 8.5, 4.9 Hz,1H), 1.26 (ddd, J=13.9, 8.7, 5.5 Hz, 1H), 0.92 (d, J=6.6 Hz, 3H), 0.89(d, J=6.5 Hz, 3H); LCMS (ESI) m/e 362.1 [(M+H)⁺, calcd C₁₉H₂₅F₁N₃O₃,362.2]; LC/MS retention time (method A): t_(R)=1.85 min.

Example 14(S)-methyl(4-(4-((2-amino-4-methylpentyl)oxy)-3-(isoxazol-5-yl)phenyl)pyridin-2-yl)carbamate

Prepared as described in Example 1.

Part A: (S)-tert-butyl(1-(4-bromo-2-(isoxazol-5-yl)phenoxy)-4-methylpentan-2-yl)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 8.31 (s, 1H), 8.09 (d, J=2.4 Hz, 1H),7.46 (dd, J=9.1, 2.6 Hz, 1H), 6.88 (d, J=9.0 Hz, 2H), 4.60 (d, J=8.9 Hz,1H), 4.19 (d, J=7.0 Hz, 1H), 4.02 (qd, J=9.2, 5.2 Hz, 2H), 1.75 (dq,J=13.6, 6.7 Hz, 1H), 1.46 (d, J=12.0 Hz, 11H), 0.98 (d, J=6.6 Hz, 6H);LCMS (ESI) m/e 461.0 [(M+Na)⁺, calcd C₂₀H₂₇Br₁N₂Na₁O₄, 461.1]; LC/MSretention time (method B): t_(R)=2.41 min.

Part B: (S)-methyl(4-(4-((2-Boc-amino-4-methylpentyl)oxy)-3-(isoxazol-5-yl)phenyl)pyridin-2-yl)carbamate

LCMS (ESI) m/e 511.4 [(M+H)⁺, calcd C₂₇H₃₅N₄O₆, 511.2]; LC/MS retentiontime (method A): t_(R)=2.27 min.

Part C: (S)-methyl(4-(4-((2-amino-4-methylpentyl)oxy)-3-(isoxazol-5-yl)phenyl)pyridin-2-yl)carbamate

Obtained (S)-methyl(4-(4-((2-amino-4-methylpentyl)oxy)-3-(isoxazol-5-yl)phenyl)pyridin-2-yl)carbamate(10.9 mg, 0.027 mmol, 34% yield for the final step) as an off-whitesolid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (d, J=1.7 Hz, 1H), 8.34 (d,J=5.2 Hz, 1H), 8.19 (t, J=2.4 Hz, 2H), 7.89 (dd, J=8.7, 2.4 Hz, 1H),7.44 (d, J=5.3 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.05 (d, J=1.9 Hz, 1H),4.18 (dd, J=9.7, 4.5 Hz, 1H), 4.09 (dd, J=9.6, 6.3 Hz, 1H), 3.72 (s,3H), 3.36 (d, J=4.3 Hz, 1H), 1.83 (dt, J=13.7, 6.7 Hz, 1H), 1.44 (dt,J=13.6, 7.0 Hz, 1H), 1.41-1.32 (m, 1H), 0.92 (dd, J=9.4, 6.6 Hz, 6H);LCMS (ESI) m/e 411.1 [(M+H)⁺, calcd C₂₂H₂₇N₄O₄, 411.2]; LC/MS retentiontime (method B): t_(R)=1.63 min.

Example 15(S)-2-((2-amino-4-methylpentyl)oxy)-5-(2-methylpyridin-4-yl)benzonitrile

Prepared as described in Example 1.

Part A: (S)-tert-butyl(1-(4-bromo-2-cyanophenoxy)-4-methylpentan-2-yl)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 7.68 (d, J=2.5 Hz, 1H), 7.64 (dd,J=8.9, 2.5 Hz, 1H), 6.91 (d, J=8.9 Hz, 1H), 4.71 (s, 1H), 4.12 (t, J=6.1Hz, 1H), 4.10-3.98 (m, 2H), 1.79-1.67 (m, 1H), 1.59 (dd, J=13.8, 6.9 Hz,2H), 1.47 (s, 9H), 0.98 (dd, J=6.5, 5.2 Hz, 6H); LCMS (ESI) m/e 397.1[(M+H)⁺, calcd C₁₈H₂₆Br₁N₂O₃, 397.1]; LC/MS retention time (method A):t_(R)=2.22 min.

Part B: (S)-tert-butyl(1-(2-cyano-4-(2-methylpyridin-4-yl)phenoxy)-4-methylpentan-2-yl)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 8.56 (d, J=5.3 Hz, 1H), 7.84 (d, J=2.3Hz, 1H), 7.80 (dd, J=8.8, 2.4 Hz, 1H), 7.31 (d, J=1.7 Hz, 1H), 7.25 (dd,J=5.3, 1.8 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 4.81 (d, J=8.6 Hz, 1H),4.21-4.11 (m, 2H), 4.10-4.03 (m, 1H), 2.64 (s, 3H), 1.76-1.68 (m, 1H),1.60 (tt, J=15.6, 6.2 Hz, 2H), 1.46 (s, 9H), 0.98 (dd, J=6.5, 5.0 Hz,6H); LCMS (ESI) m/e 410.2 [(M+H)⁺, calcd C₂₄H₃₂N₃O₃, 410.2]; LC/MSretention time (method A): t_(R)=2.18 min.

Part C:(S)-2-((2-amino-4-methylpentyl)oxy)-5-(2-methylpyridin-4-yl)benzonitrile

Obtained (48.4 mg, 0.152 mmol, 99% yield for the final step) as anoff-white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.49 (d, J=5.3 Hz, 1H),8.24 (d, J=2.4 Hz, 1H), 8.11 (dd, J=8.9, 2.4 Hz, 1H), 7.65 (s, 1H),7.57-7.52 (m, 1H), 7.38 (d, J=8.9 Hz, 1H), 4.09 (dd, J=9.5, 5.1 Hz, 1H),4.01 (dd, J=9.5, 6.2 Hz, 1H), 3.16 (dq, J=10.8, 5.4 Hz, 1H), 2.53 (s,3H), 2.51 (s, 2H), 1.83 (dq, J=12.8, 6.5 Hz, 1H), 1.39 (ddd, J=13.5,8.4, 5.1 Hz, 1H), 1.30 (ddd, J=13.8, 8.6, 5.9 Hz, 1H), 0.93 (d, J=6.6Hz, 3H), 0.89 (d, J=6.6 Hz, 3H); LCMS (ESI) m/e 310.1 [(M+H)⁺, calcdC₁₉H₂₄N₃O₁, 310.2]; LC/MS retention time (method A): t_(R)=1.82 min.

Example 16(S)-2-((2-amino-4-methylpentyl)oxy)-5-(2-methoxypyridin-4-yl)benzonitrile

Prepared as described in Example 1.

Part A: (S)-tert-butyl(1-(2-cyano-4-(2-methylpyridin-4-yl)phenoxy)-4-methoxypentan-2-yl)carbamate

¹H NMR (500 MHz, Chloroform-d) δ 8.20 (dd, J=5.4, 0.7 Hz, 1H), 7.79 (d,J=2.3 Hz, 1H), 7.76 (dd, J=8.7, 2.4 Hz, 1H), 7.11-7.05 (m, 1H), 7.00(dd, J=5.4, 1.6 Hz, 1H), 6.85 (dd, J=1.6, 0.7 Hz, 1H), 4.84 (d, J=8.7Hz, 1H), 4.20-4.14 (m, 1H), 4.11 (ddd, J=8.7, 4.6, 2.5 Hz, 1H),4.07-4.03 (m, 1H), 3.97 (s, 3H), 1.76-1.66 (m, 1H), 1.64-1.52 (m, 2H),1.44 (s, 9H), 0.96 (dd, J=6.6, 5.7 Hz, 6H); LCMS (ESI) m/e 426.2[(M+H)⁺, calcd C₂₄H₃₂N₃O₄, 426.2]; LC/MS retention time (method A):t_(R)=2.27 min.

Part B:(S)-2-((2-amino-4-methylpentyl)oxy)-5-(2-methoxypyridin-4-yl)benzonitrile

Obtained(S)-2-((2-amino-4-methylpentyl)oxy)-5-(2-methoxypyridin-4-yl)benzonitrile(28.6 mg, 0.088 mmol, 60% yield for the final step) as an off-whitesolid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.23 (dd, J=6.7, 3.9 Hz, 2H), 8.10(dd, J=8.9, 2.4 Hz, 1H), 7.41-7.32 (m, 2H), 7.18 (s, 1H), 4.05 (dd,J=9.3, 5.1 Hz, 1H), 3.98 (dd, J=9.4, 6.3 Hz, 1H), 3.90 (s, 3H), 3.12(dq, J=10.4, 5.4 Hz, 1H), 1.83 (tt, J=13.3, 6.7 Hz, 1H), 1.36 (ddd,J=13.4, 8.5, 4.9 Hz, 1H), 1.26 (ddd, J=13.9, 8.8, 5.7 Hz, 1H), 0.92 (d,J=6.6 Hz, 3H), 0.89 (d, J=6.6 Hz, 3H); LCMS (ESI) m/e 326.1 [(M+H)⁺,calcd C₁₉H₂₄N₃O₂, 326.2]; LC/MS retention time (method A): t_(R)=1.88min.

Example 17(S)-2-((2-amino-4-methylpentyl)oxy)-5-(2-(trifluoromethyl)pyridin-4-yl)benzonitrile

Prepared as described in Example 1.

Part A: (S)-tert-butyl(1-(2-cyano-4-(2-(trifluoromethyl)pyridin-4-yl)phenoxy)-4-methylpentan-2-yl)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 8.80 (d, J=5.1 Hz, 1H), 7.89 (d, J=2.4Hz, 1H), 7.86 (dd, J=8.8, 2.5 Hz, 1H), 7.84-7.80 (m, 1H), 7.64 (dd,J=5.1, 1.8 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 4.79 (d, J=8.5 Hz, 1H),4.26-4.14 (m, 2H), 4.11-4.04 (m, 1H), 1.73 (p, J=6.5 Hz, 1H), 1.66-1.54(m, 2H), 1.46 (s, 9H), 0.98 (t, J=6.3 Hz, 6H); ¹⁹F NMR (376 MHz,Chloroform-d) δ −68.06; LCMS (ESI) m/e 486.2 [(M+Na)⁺, calcdC₂₄H₂₈F₃NaN₃O₃, 486.2]; LC/MS retention time (method B): t_(R)=2.35 min.

Part B:(S)-2-((2-amino-4-methylpentyl)oxy)-5-(2-(trifluoromethyl)pyridin-4-yl)benzonitrile

Obtained(S)-2-((2-amino-4-methylpentyl)oxy)-5-(2-(trifluoromethyl)pyridin-4-yl)benzonitrile(34.3 mg, 0.093 mmol, 93% yield for the final step) as an off-whitesolid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.81 (d, J=5.2 Hz, 1H), 8.46 (d,J=2.9 Hz, 1H), 8.34-8.21 (m, 2H), 8.11 (d, J=5.1 Hz, 1H), 7.42 (d, J=8.9Hz, 1H), 4.08 (dd, J=9.9, 5.2 Hz, 1H), 4.05-3.95 (m, 1H), 3.13 (d, J=7.5Hz, 1H), 1.85 (t, J=7.0 Hz, 1H), 1.43-1.32 (m, 1H), 1.27 (q, J=11.7, 9.8Hz, 1H), 0.93 (d, J=6.4 Hz, 3H), 0.89 (d, J=6.4 Hz, 3H); LCMS (ESI) m/e364.1 [(M+H)⁺, calcd C₁₉H₂F₃N₃O₁, 364.2]; LC/MS retention time (methodB): t_(R)=1.97 min.

Example 18(S)-1-(2-(isoxazol-5-yl)-4-(2-methylpyridin-4-yl)phenoxy)-4-methylpentan-2-amine

Prepared as described in Example 1.

Part A: (S)-tert-butyl(1-(2-(isoxazol-5-yl)-4-(2-methylpyridin-4-yl)phenoxy)-4-methylpentan-2-yl)carbamate

LCMS (ESI) m/e 452.1 [(M+H)⁺, calcd C₂₆H₃₄N₃O₄, 452.2]; LC/MS retentiontime (method B): t_(R)=2.03 min.

Part B:(S)-1-(2-(isoxazol-5-yl)-4-(2-methylpyridin-4-yl)phenoxy)-4-methylpentan-2-amine

Obtained(S)-1-(2-(isoxazol-5-yl)-4-(2-methylpyridin-4-yl)phenoxy)-4-methylpentan-2-amine(14.6 mg, 0.041 mmol, 49% yield for the final step) as an off-whitesolid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.72 (d, J=1.9 Hz, 1H), 8.49 (d,J=5.3 Hz, 1H), 8.24 (d, J=2.4 Hz, 1H), 7.93 (dd, J=8.8, 2.4 Hz, 1H),7.65 (s, 1H), 7.59-7.52 (m, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.03 (d, J=1.9Hz, 1H), 4.12 (dd, J=9.6, 4.6 Hz, 1H), 4.04 (dd, J=9.5, 6.3 Hz, 1H),3.27 (dq, J=10.3, 5.3 Hz, 1H), 2.51 (s, 3H), 1.83 (dt, J=14.0, 6.7 Hz,1H), 1.40 (ddd, J=13.4, 8.4, 5.2 Hz, 1H), 1.32 (ddd, J=13.7, 8.5, 5.7Hz, 1H), 0.91 (dd, J=10.5, 6.5 Hz, 6H); LCMS (ESI) m/e 352.1 [(M+H)⁺,calcd C₂₁H₂₆N₃O₂, 352.2]; LC/MS retention time (method B): t_(R)=1.50min.

Example 19(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide

Part A:(S)-1-(4-bromo-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

To a 50 mL round-bottomed flask was added(S)-2-amino-2,4-dimethylpentan-1-ol (66.1 mg, 0.504 mmol) intetrahydrofuran (1.5 mL) to give a colorless solution. Potassiumtert-butoxide (0.604 mL, 0.604 mmol) (1.0 M in THF) was added dropwiseunder nitrogen. After 5 min, 4-bromo-1-fluoro-2-(trifluoromethyl)benzene(0.079 mL, 0.604 mmol) was added in one portion. The mixture was stirredat rt for 2 h. The reaction was quenched with water and extracted withEtOAc. The organic layer was washed with brine, dried (Na₂SO₄) andconcentrated under reduced pressure to obtain crude(S)-1-(4-bromo-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(146 mg, 0.412 mmol, 82% yield) as a tan oil which was used as is. ¹HNMR (500 MHz, Chloroform-d) δ 7.70 (d, J=2.5 Hz, 1H), 7.59 (dd, J=8.8,2.5 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 3.80-3.72 (m, 2H), 1.83-1.73 (m,1H), 1.53-1.44 (m, 2H), 1.23 (s, 3H), 0.98 (dd, J=12.2, 6.7 Hz, 6H); ¹⁹FNMR (470 MHz, Chloroform-d) δ −62.61; LCMS (ESI) m/e 354.0 [(M+H)⁺,calcd C₁₄H₂₀Br₁F₃N₁O₁, 354.1]; LC/MS retention time (method B):t_(R)=2.14 min.

Part B:(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide

To a 2 mL vial was added(S)-1-(4-bromo-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(43.5 mg, 0.123 mmol),N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide(26.5 mg, 0.147 mmol) (prepared as described in Example 1, Part A), andNa₂CO₃ (0.184 mL, 0.368 mmol) in dioxane (0.5 mL) under nitrogen to givea colorless suspension. 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, toluene (5.05 mg, 6.14 μmol) was added undernitrogen. The vial was sealed and heated at 130° C. (microwave) for 2 h(100° C. oil heating for 2 h was fine and was used for all otherexamples). The mixture was cooled to rt and diluted with EtOAc thenpassed through a plug of Na₂SO₄. The organic solution was concentratedunder reduced pressure. The residue was purified by reverse phase HPLC(acetonitrile: water with 10 mM ammonium) to give(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide(24 mg, 0.057 mmol, 47% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.58 (s, 1H), 8.36 (d, J=5.2 Hz, 2H), 7.97 (t, J=8.1 Hz,1H), 7.89 (s, 1H), 7.44 (d, J=5.4 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 3.86(q, J=8.8 Hz, 2H), 2.13 (s, 3H), 1.79 (dq, J=10.2, 5.2, 4.0 Hz, 1H),1.39 (d, J=5.5 Hz, 2H), 1.12 (s, 3H), 0.91 (d, J=6.6 Hz, 6H); LCMS (ESI)m/e 410.2 [(M−H), calcd C₂H₂₃F₃N₃O₂, 410.2]; LC/MS retention time(method B): t_(R)=1.87 min.

Example 20(S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)carbamate

Prepared as described in Example 19 to obtain (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)carbamate(22.9 mg, 0.051 mmol, 38% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.29 (s, 1H), 8.32 (d, J=5.3 Hz, 1H), 8.11 (s, 1H), 7.99 (d,J=8.7 Hz, 1H), 7.90 (s, 1H), 7.39 (dd, J=12.5, 7.0 Hz, 2H), 3.87 (q,J=8.8 Hz, 2H), 3.71 (s, 3H), 1.79 (dq, J=10.8, 5.6, 4.8 Hz, 1H), 1.40(d, J=5.6 Hz, 2H), 1.13 (s, 3H), 0.91 (d, J=6.6 Hz, 6H); LCMS (ESI) m/e426.3 [(M−H)⁺, calcd C₂₁H₂₇F₃N₃O₃, 426.2]; LC/MS retention time (methodA): t_(R)=2.23 min.

Example 21(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide

Prepared as described in Example 19

Part A: (S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-bromobenzonitrile

¹H NMR (400 MHz, Chloroform-d) δ 7.68 (d, J=2.5 Hz, 1H), 7.63 (dd,J=8.9, 2.4 Hz, 1H), 6.86 (d, J=9.0 Hz, 1H), 3.84-3.77 (m, 2H), 1.87-1.74(m, 1H), 1.59-1.53 (m, 2H), 1.27 (s, 3H), 1.00 (dd, J=8.3, 6.6 Hz, 6H);LCMS (ESI) m/e 311.1, 313.1 Br pattern [(M+H)⁺, calcd Cl₄H₂₀BrN₂O,311.1]; LC/MS retention time (method A): t_(R)=2.01 min.

Part B:(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide

Obtained(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide(28.9 mg, 0.078 mmol, 70% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.58 (s, 1H), 8.44-8.29 (m, 2H), 8.12 (s, 1H), 8.00 (d,J=8.9 Hz, 1H), 7.44 (d, J=5.3 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 3.91 (t,J=6.7 Hz, 2H), 2.13 (s, 3H), 1.82 (p, J=6.2 Hz, 1H), 1.43 (t, J=5.4 Hz,2H), 1.15 (s, 3H), 0.93 (dd, J=6.7, 3.7 Hz, 6H); LCMS (ESI) m/e 367.3[(M+H)⁺, calcd C₂₁H₂₇N₄O₂, 367.2]; LC/MS retention time (method A):t_(R)=1.82 min.

Example 22(S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)carbamate

Prepared as described in Example 19 to obtain (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)carbamate(21.1 mg, 0.053 mmol, 47% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.29 (s, 1H), 8.32 (d, J=5.3 Hz, 1H), 8.13 (s, 1H), 8.10 (s,1H), 8.01 (d, J=9.1 Hz, 1H), 7.40 (dd, J=11.9, 7.1 Hz, 2H), 3.91 (t,J=6.5 Hz, 2H), 3.71 (s, 3H), 1.81 (dq, J=12.5, 6.2 Hz, 1H), 1.42 (q,J=8.2, 6.6 Hz, 2H), 1.15 (s, 3H), 0.93 (dd, J=6.8, 3.8 Hz, 6H); LCMS(ESI) m/e 405.2 [(M+Na)⁺, calcd C₂₁H₂₆N₄Na₁O₃, 405.2]; LC/MS retentiontime (method B): t_(R)=1.87 min.

Example 23(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(difluoromethyl)phenyl)pyridin-2-yl)acetamide

Prepared as described in Example 19.

Part A:(S)-1-(4-bromo-2-(difluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

¹H NMR (400 MHz, Chloroform-d) δ 7.67 (dd, J=2.4, 1.1 Hz, 1H), 7.53(ddt, J=8.8, 2.3, 1.1 Hz, 1H), 6.93-6.70 (m, 2H), 3.79-3.72 (m, 2H),1.85-1.73 (m, 1H), 1.52-1.47 (m, 2H), 1.23 (s, 3H), 0.99 (dd, J=7.6, 6.6Hz, 6H); ¹⁹F NMR (376 MHz, Chloroform-d) δ −116.21; LCMS (ESI) m/e 336.1[(M+H)⁺, calcd C₁₄H₂₁Br₁F₂N₁O₁, 336.1]; LC/MS retention time (method A):t_(R)=2.18 min.

Part B:(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(difluoromethyl)phenyl)pyridin-2-yl)acetamide

Obtained(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(difluoromethyl)phenyl)pyridin-2-yl)acetamide(13 mg, 0.033 mmol, 32% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.56 (s, 1H), 8.45-8.29 (m, 2H), 7.87 (d, J=8.7 Hz, 1H),7.82 (s, 1H), 7.49-7.12 (m, 3H), 3.84 (s, 2H), 2.13 (s, 3H), 1.79 (dt,J=14.1, 7.3 Hz, 1H), 1.47-1.34 (m, 2H), 1.14 (s, 3H), 0.92 (dd, J=11.3,6.6 Hz, 6H); LCMS (ESI) m/e 392.3 [(M+H)⁺, calcd C₂₁H₂F₂N₃O₂, 392.2];LC/MS retention time (method A): t_(R)=1.90 min.

Example 24 (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(difluoromethyl)phenyl)pyridin-2-yl)carbamate

Prepared as described in Example 19 to obtain (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(difluoromethyl)phenyl)pyridin-2-yl)carbamate(15.4 mg, 0.037 mmol, 35% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.26 (s, 1H), 8.31 (d, J=5.3 Hz, 1H), 8.11 (s, 1H),7.91-7.85 (m, 1H), 7.83 (s, 1H), 7.42-7.13 (m, 3H), 3.84 (s, 2H), 3.70(s, 3H), 1.79 (dt, J=12.8, 6.4 Hz, 1H), 1.41 (qd, J=14.0, 5.6 Hz, 2H),1.14 (s, 3H), 0.92 (dd, J=11.4, 6.6 Hz, 6H); LCMS (ESI) m/e 408.3[(M+H)⁺, calcd C₂₁H₂₈F₂N₃O₃, 408.2]; LC/MS retention time (method A):t_(R)=2.00 min.

Example 25(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamide

Prepared as described in Example 19.

Part A:(S)-1-(4-bromo-2-(trifluoromethoxy)phenoxy)-2,4-dimethylpentan-2-amine

¹H NMR (400 MHz, Chloroform-d) δ 7.41-7.34 (m, 2H), 6.87 (d, J=8.6 Hz,1H), 3.76-3.72 (m, 2H), 1.83-1.76 (m, 1H), 1.49-1.47 (m, 2H), 1.23 (s,3H), 1.01-0.98 (m, 6H); ¹⁹F NMR (376 MHz, Chloroform-d) δ −58.22; LCMS(ESI) m/e 370.1 [(M+H)⁺, calcd C₁₄H₂₀Br₁F₃N₁O₂, 370.1]; LC/MS retentiontime (method A): t_(R)=2.33 min.

Part B:(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamide

Obtained(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamide(14.1 mg, 0.032 mmol, 36% yield) as an off-white as solid. ¹H NMR (500MHz, DMSO-d₆) δ 10.57 (s, 1H), 8.35 (d, J=4.6 Hz, 2H), 7.74 (d, J=8.8Hz, 1H), 7.70 (s, 1H), 7.41 (d, J=5.1 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H),3.83 (t, J=7.3 Hz, 2H), 2.12 (s, 3H), 1.81 (dt, J=13.1, 6.7 Hz, 1H),1.39 (q, J=7.6, 6.3 Hz, 2H), 1.13 (s, 3H), 0.92 (t, J=5.1 Hz, 6H); LCMS(ESI) m/e 426.2 [(M+H)⁺, calcd C₂₁H₂₇F₃N₃O₃, 426.2]; LC/MS retentiontime (method A): t_(R)=2.08 min.

Example 26 (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethoxy)phenyl)pyridin-2-yl)carbamate

Prepared as described in Example 19 to obtain (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethoxy)phenyl)pyridin-2-yl)carbamate(11.5 mg, 0.026 mmol, 27% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.28 (s, 1H), 8.31 (d, J=5.2 Hz, 1H), 8.10 (s, 1H), 7.75 (d,J=8.6 Hz, 1H), 7.71 (s, 1H), 7.43-7.34 (m, 2H), 3.86-3.80 (m, 2H), 3.71(s, 3H), 1.81 (dt, J=12.7, 6.4 Hz, 1H), 1.39 (q, J=8.2, 6.3 Hz, 2H),1.13 (s, 3H), 0.92 (dd, J=6.7, 3.8 Hz, 6H); LCMS (ESI) m/e 442.2[(M+H)⁺, calcd C₂₁H₂₇F₃N₃O₄, 442.2]; LC/MS retention time (method B):t_(R)=2.00 min.

Example 27(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)acetamide

Prepared as described in Example 19.

Part A: (S)-1-(2-fluorophenoxy)-2,4-dimethylpentan-2-amine

LCMS (ESI) m/e 226.3 [(M+H)⁺, calcd C₁₃H₂₁F₁N₁O₁, 226.2]; LC/MSretention time (method B): t_(R)=1.93 min.

Part B:(S)-1-(4-bromo-2-(trifluoromethoxy)phenoxy)-2,4-dimethylpentan-2-amine

To a 100 mL round-bottomed flask was added(S)-1-(2-fluorophenoxy)-2,4-dimethylpentan-2-amine (83.4 mg, 0.370 mmol)in CHCl₃ (2 mL) to give a colorless solution. Br₂ (0.021 mL, 0.407 mmol)was added. The mixture was stirred at 45° C. for 15 h. The reactionmixture cooled to rt and was diluted with EtOAc then treated withaqueous sodium bisulfite solution. The layers were separated. Theorganic layer was washed with water, brine, dried (Na₂SO₄) andconcentrated under reduced pressure to afford(S)-1-(4-bromo-2-(trifluoromethoxy)phenoxy)-2,4-dimethylpentan-2-amine(84 mg, 0.276 mmol, 75% yield). The crude material was carried on as is.LCMS (ESI) m/e 304.1 [(M+H)⁺, calcd C₁₃H₂Br₁F₁N₁O₁, 304.1]; LC/MSretention time (method A): t_(R)=2.05 min.

Part C:(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)acetamide

Obtained(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)acetamide(14.5 mg, 0.039 mmol, 31% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.55 (s, 1H), 8.33 (d, J=6.0 Hz, 2H), 7.61 (d, J=12.3 Hz,1H), 7.52 (d, J=8.8 Hz, 1H), 7.39 (d, J=5.4 Hz, 1H), 7.30 (t, J=8.8 Hz,1H), 3.84-3.76 (m, 2H), 2.12 (s, 3H), 1.81 (p, J=6.4 Hz, 1H), 1.38 (q,J=7.9, 6.8 Hz, 2H), 1.12 (s, 3H), 0.93 (t, J=6.6 Hz, 6H); LCMS (ESI) m/e360.2 [(M+H)⁺, calcd C₂₀H₂₇F₁N₃O₂, 360.2]; LC/MS retention time (methodA): t_(R)=1.82 min.

Example 28 (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)carbamate

Prepared as described in Example 19 to obtain (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)carbamate(17.1 mg, 0.044 mmol, 30% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.25 (s, 1H), 8.29 (d, J=5.3 Hz, 1H), 8.09 (s, 1H), 7.62 (d,J=12.4 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.36 (d, J=5.4 Hz, 1H), 7.30 (t,J=8.7 Hz, 1H), 3.82 (d, J=2.8 Hz, 2H), 3.70 (s, 3H), 1.86-1.74 (m, 1H),1.46-1.33 (m, 2H), 1.13 (s, 3H), 0.93 (t, J=6.8 Hz, 6H); LCMS (ESI) m/e376.2 [(M+H)⁺, calcd C₂₀H₂₇F₁N₃O₃, 376.2]; LC/MS retention time (methodA): t_(R)=1.92 min.

Example 29 methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)pyridin-2-yl)carbamate

Part A: Benzyl(1-(4-bromo-2-chlorophenoxy)-2,4-dimethylpentan-2-yl)carbamate

An NMP (0.3 mL) suspension of 4-bromo-2-chlorophenol (0.074 g, 0.354mmol), potassium carbonate (0.037 g, 0.266 mmol) and benzyl4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(0.058 g, 0.177 mmol) was heated at 50° C. overnight. The reaction wasdiluted with ethyl acetate and washed with NaOH (1N) (2×) and water(1×). The ethyl acetate layer was separated, dried (Na₂SO₄), filteredand concentrated under reduced pressure. The crude material was carriedon without further purification. LCMS (ESI) m/e 476.1 [(M+Na)⁺, calcdC₂₁H₂₅BrClNaNO₃, 476.1]; LC/MS retention time (method B): t_(R)=2.56min.

Part B: Cbz methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)pyridin-2-yl)carbamate

A mixture of sodium carbonate (0.177 ml, 0.354 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (10.12 mg, 0.012 mmol),(2-((methoxycarbonyl)amino)pyridin-4-yl)boronic acid (0.035 g, 0.177mmol) and benzyl(1-(4-bromo-2-chlorophenoxy)-2,4-dimethylpentan-2-yl)carbamate (0.080 g,0.177 mmol) in dioxane (1 mL) (degassed) was heated at 85° C. overnight.The reaction was diluted with ethyl acetate and washed with water (3×).The aqueous layer was extract with ethyl acetate. The ethyl acetatelayers were combined, washed with brine, dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The residue was purified via silicagel chromatography (from 0 to 30% ethyl acetate in hexanes) to give Cbzmethyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)pyridin-2-yl)carbamate(56.5 mg, 0.107 mmol, 61% yield for two steps) as a tan foam. (0.565 g,61% yield). LCMS (ESI) m/e 548.2 [(M+Na)⁺, calcd C₂₈H₃₂ClN₃O₅Na, 548.2];LC/MS retention time (method B): t_(R)=2.25 min.

Part C: methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)pyridin-2-yl)carbamate

Triethylsilane(0.026 mL, 0.161 mmol) was added to a CH₂Cl₂ (0.5 mL)suspension of palladium(II) acetate (2.2 mg, 9.80 μmol) andtriethylamine (1 drop) at rt. This solution was stirred at roomtemperature for 10 min before the addition of a CH₂Cl₂ (0.5 mL) solutionof Cbz protected methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)pyridin-2-yl)carbamate(0.0565 g, 0.107 mmol) (the flask contain the Cbz protected methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)pyridin-2-yl)carbamate(0.0565 g, 0.107 mmol) was rinsed with CH₂Cl₂ (0.5 mL) and added to thereaction mixture). The above reaction was stirred at room temperatureovernight. The solvent was removed under reduced pressure and theresidue was purified via reverse phase HPLC (acetonitrile/water/10 nMammonium acetate) to afford methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)pyridin-2-yl)carbamate(29.6 mg, 0.076 mmol, 70% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.27 (br. s., 1H), 8.30 (d, J=5.2 Hz, 1H), 8.08 (s, 1H),7.79 (s, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.37 (d, J=5.2 Hz, 1H), 7.26 (d,J=8.5 Hz, 1H), 3.82 (d, J=2.4 Hz, 2H), 3.70 (s, 3H), 1.85-1.77 (m, 1H),1.42 (br. s., 2H), 1.14 (s, 3H), 0.92 (m, 6H); LCMS (ESI) m/e 392.2[(M+H)⁺, calcd C₂₀H₂₇ClN₃O₃, 392.2]; LC/MS retention time (method B):t_(R)=1.75 min.

Example 30 methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-methylphenyl)pyridin-2-yl)carbamate

Prepared as described in Example 29.

Part A: Benzyl(1-(4-bromo-2-methylphenoxy)-2,4-dimethylpentan-2-yl)carbamate

LCMS (ESI) m/e 456.1 [(M+Na)⁺, calcd C₂₂H₂₈BrNO₃Na, 456.1]; LC/MSretention time (method B): t_(R)=2.56 min.

Part B: Cbz methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-methylphenyl)pyridin-2-yl)carbamate

LCMS (ESI) m/e 506.1 [(M+H)⁺, calcd C₂₉H₃₆N₃O₅, 506.3]; LC/MS retentiontime (method B): t_(R)=2.21 min.

Part C:methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-methylphenyl)pyridin-2-yl)carbamate

Obtainedmethyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-methylphenyl)pyridin-2-yl)carbamate(3.7 mg, 9.96 umol, 35% yield) as an off white solid. ¹H NMR (600 MHz,DMSO-d₆) δ 10.11 (br. s., 1H), 8.26 (d, J=5.1 Hz, 1H), 8.08 (s, 1H),7.53 (br. s., 2H), 7.34-7.27 (m, 1H), 7.03 (d, J=9.2 Hz, 1H), 3.77-3.68(m, 5H), 2.28 (s, 3H), 1.86-1.76 (m, 1H), 1.42 (t, J=5.0 Hz, 2H), 1.14(s, 3H), 0.93 (m, 6H); LCMS (ESI) m/e 372.3 [(M+H)⁺, calcd C₂₁H₃₀N₃O₃,372.2]; LC/MS retention time (method B): t_(R)=1.71 min.

Example 31 methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-2,3-dimethylphenyl)pyridin-2-yl)carbamate

Prepared as described in Example 29.

Part A: Benzyl(1-((5-chloro-3,4-dimethylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

LCMS (ESI) m/e 426.3 [(M+Na)⁺, calcd C₂₂H₂₉ClN₂O₃Na, 427.2]; LC/MSretention time (method B t_(R)=2.57 min.

Part B: Cbz methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-2,3-dimethylphenyl)pyridin-2-yl)carbamate

A mixture of 2^(nd) generation Xphos Precatalyst (4 mg, 5.08 μmol),potassium phosphate tribasic (0.5 mL, 0.250 mmol),(2-((methoxycarbonyl)amino)pyridin-4-yl)boronic acid (0.044 g, 0.225mmol) and benzyl(1-(4-chloro-2,3-dimethylphenoxy)-2,4-dimethylpentan-2-yl)carbamate(0.0385 g, 0.095 mmol) in THE (0.8 mL) was degassed via vacuum/N₂ fillcycle three times. The reaction mixture was heated at 80° C. overnight.The reaction was diluted with ethyl acetate and washed with water (2×)followed by brine. The ethyl acetate layer was separated, dried(Na₂SO₄), filtered and concentrated under reduced pressure. The productwas purified via silica gel chromatography (0-30% ethyl acetate inhexanes) to afford Cbz methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-2,3-dimethylphenyl)pyridin-2-yl)carbamate(25 mg, 0.025 mmol, 27% yield) as a white solid. LCMS (ESI) m/e 520.5[(M+H)⁺, calcd C₃H₃₇N₃O₅, 520.3]; LC/MS retention time (method A):t_(R)=2.38 min.

Part C: methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-2,3-dimethylphenyl)pyridin-2-yl)carbamate

A mixture of Pd/C (6 mg, 5.64 μmol) and Cbz protected methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-2,3-dimethylphenyl)pyridin-2-yl)carbamate(0.025 g, 0.048 mmol) in ethanol (4 mL) was hydrogenated via a H₂balloon at room temperature overnight. The reaction mixture was filteredthrough a celite pad and washed with CH₂Cl₂. The filtrate wasconcentrated under reduced pressure and the residue was purified byreverse phase HPLC (acetonitrile/water/10 mM ammonium acetate) to affordmethyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-2,3-dimethylphenyl)pyridin-2-yl)carbamate(2.8 mg, 7.26 umol, 15% yield) as an off-white solid. ¹H NMR (600 MHz,DMSO-d₆) δ 8.26 (d, J=4.8 Hz, 1H), 7.74 (s, 1H), 7.02 (d, J=8.4 Hz, 1H),6.96 (d, J=5.1 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 3.67 (s, 4H), 3.48 (d,J=10.6 Hz, 1H), 2.19 (s, 3H), 1.84 (s, 3H), 1.83-1.74 (m, 1H), 1.42 (t,J=6.1 Hz, 2H), 1.14 (s, 3H), 0.92 (t, J=5.9 Hz, 6H). LCMS (ESI) m/e369.2 [(M−NH₂)⁻, calcd C₂₂H₂₉N₂O₃, 369.2]; LC/MS retention time (methodB): t_(R)=1.68 min.

Example 32 (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(hydroxymethyl)phenyl)pyridin-2-yl)carbamate

Part A. 4-methyl-5H-1,2,3-oxathiazole 2,2-dioxide

Step 1: Sulfamoyl chloride formation: In a 1000 ml 4 neck round-bottomedflask equipped with a mechanical stirring and an addition funnel, wascharged DCM (400 mL) and chlorosulfonyl isocyanate (124 mL, 1430 mmol).Under N₂, this solution was cooled to 0° C. Then formic acid (53.9 mL,1430 mmol) was added to DCM (100 mL) and this solution was transferredto the addition funnel and the solution was added slowly to thevigorously stirring reaction mixture. Gradually a thick slurry formed. Aslow exotherm was observed so additional dry ice was added to acetonebath. Once temperature was stabilized, addition of the formic acid wascontinued. Addition was done in ˜25 min. The mixture was allowed togradually warm to room temperature and was stirred overnight.

Step 2: In a separate 5 L 4 neck reaction flask was chargedhydroxyacetone (72.5 mL, 953 mmol), pyridine (116 mL, 1430 mmol), andDCM (2000 mL). This solution was cooled to −5° C. under N₂. Thesulfamoyl chloride solution was added slowly via Teflon tube over 10min. After the addition, the reaction was stirred for 15 min then theice bath was removed and the reaction mixture allowed to warm to roomtemperature. As the reaction progressed, a gummy material formed. Thematerial was purified via silica gel chromatography (300 g silica geleluting with DCM). Obtained 4-methyl-5H-1,2,3-oxathiazole 2,2-dioxide(72.4 g, 536 mmol, 56% yield) as a colorless solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ 5.09 (s, 2H), 2.44 (s, 3H); LCMS (ESI) m/e 136.0[(M+H)⁺, calcd for C₃H₆NO₃S 136.0].

Part B. 2-(tert-butoxycarbonylamino)-2,4-dimethylpentanoic acid4-methyl-4-(2-methylallyl)-1,2,3-oxathiazolidine 2,2-dioxide

A suspension of 4-methyl-5H-1,2,3-oxathiazole 2,2-dioxide (0.541 g, 4mmol) in methyl tert-butyl ether (30 mL) was cooled below 0° C. with anice/IPA bath. To the cooled solution was added a solution of(2-methylallyl)magnesium chloride, 0.5 M in THE (9.60 mL, 4.80 mmol).The reaction mixture was allowed to warm to rt overnight. It was thenquenched with a saturated solution of NH₄Cl (50 mL) and EtOAc (20 mL)was added. The organic phase was separated, washed with brine (50 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive 2-(tert-butoxycarbonylamino)-2,4-dimethylpentanoic acid4-methyl-4-(2-methylallyl)-1,2,3-oxathiazolidine 2,2-dioxide (0.567 g,2.96 mmol, 74% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 5.06 (quin,J=1.5 Hz, 1H), 4.87 (dd, J=1.7, 0.8 Hz, 1H), 4.50 (br. s., 1H), 4.40 (d,J=8.6 Hz, 1H), 4.29 (d, J=8.7 Hz, 1H), 2.56 (d, J=13.8 Hz, 1H),2.40-2.30 (m, 1H), 1.86 (br. s, 3H), 1.49 (s, 3H); LCMS (ESI) m/e 192.1[(M+H)⁺, calcd for C₇H₁₄NO₃S 192.1].

Part C. benzyl4-methyl-4-(2-methylallyl)-1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide

To a N₂ flushed, 100 mL round-bottomed flask was added a solution of4-methyl-4-(2-methylallyl)-1,2,3-oxathiazolidine 2,2-dioxide (0.55 g,2.88 mmol) in THE (10 mL). A solution of potassium tert-butoxide (4.31mL, 4.31 mmol) in THE was added The temperature rose to 27° C. and thesolution became a suspension. The mixture was stirred at roomtemperature for 1 h. Benzyl carbonochloridate (1.026 mL, 7.19 mmol) wasadded slowly. The reaction mixture was stirred at room temperature for 2h. The reaction mixture was then quenched with water (50 mL) andextracted with EtOAc (2×70 mL). The organic extracts were washed withbrine (50 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography(ethyl acetate/hexanes) to give benzyl4-methyl-4-(2-methylallyl)-1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide (0.66 g, 2.028 mmol, 71% yield). ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.58-7.32 (m, 5H), 5.43-5.25 (m, 2H), 5.01 (t, J=1.5 Hz,1H), 4.81 (d, J=0.9 Hz, 1H), 4.63 (d, J=9.5 Hz, 1H), 4.21 (d, J=9.5 Hz,1H), 2.87 (d, J=14.1 Hz, 1H), 2.56 (d, J=14.1 Hz, 1H), 1.78 (br. s, 3H),1.64 (s, 3H); LCMS (ESI) m/e 326.1 [(M+H)⁺, calcd for C₁₅H₂₀NO₅S 326.1].

The racmeic compounds was separated by chiral super critical fluidchromatography (Column: OJ-H (3×25 cm, 5 μm); Mobile Phase: CO₂/MeOH(90/10)) to give the two enantiomers.

Analytical super critical fluid chromatography conditions: Column: OJ-H(0.46×25 cm, 5 μm); BPR pressure: 100 bars; Temperature: 35° C.; Flowrate: 3.0 mL/min; Mobile Phase: CO₂/MeOH (90/10); Detector Wavelength:UV 200-400 nm

Enantiomer 1: (S)-benzyl4-methyl-4-(2-methylallyl)-1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide HPLC retention time=2.53 min.

Enantiomer 2: (R)-benzyl4-methyl-4-(2-methylallyl)-1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide HPLC retention time=2.97 min.

Part D. (S)-4-isobutyl-4-methyl-1,2,3-oxathiazolidine 2,2-dioxide

To a stirred solution of (S)-benzyl4-methyl-4-(2-methylallyl)-1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide (800 mg, 2.459 mmol) in MeOH (20 mL) was added Pd/C (262 mg,0.246 mmol) under a nitrogen atmosphere and the reaction mixture wasstirred under 1 atm hydrogen pressure for 16 h. The reaction mixture waspassed through celite pad and the celite pad was washed with EtOAc (15mL). The organic layer was evaporated under reduced pressure to afford(S)-4-isobutyl-4-methyl-1,2,3-oxathiazolidine 2,2-dioxide (462 mg, 2.39mmol, 97% yield, 95% purity) as colorless oil. The material was carriedforward without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.69 (br, 1H) 4.33 (d, J=8.03 Hz, 1H) 4.17-4.26 (m, 1H) 1.68-1.81 (m,1H) 1.53-1.63 (m, 1H) 1.43-1.51 (m, 1H) 1.34 (s, 3H) 0.81-1.00 (m, 6H).

Part E. (S)-tert-butyl4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

To a stirred solution of (S)-4-isobutyl-4-methyl-1,2,3-oxathiazolidine2,2-dioxide (7 g, 15.21 mmol) in DCM (70 mL) cooled to 0° C. was addedDMAP (1.858 g, 15.21 mmol) and (BOC)₂O (5.30 mL, 22.82 mmol) Thereaction mixture was stirred at rt for 12 h. The reaction mixture wastransfers to a separating funnel containing water (20 ml) and wasextracted with DCM (2×60 ml). The combined organic layers were washedwith brine (50 mL), dried over (Na₂SO₄), and concentrated under reducedpressure. The residue was purified via silica gel chromatography (30%ethyl acetate in pet ether) to afford (S)-tert-butyl4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (4.4g, 14.70 mmol, 97% yield) as a colorless oil. ¹H NMR (400 MHz,CHLOROFORM-d) δ 4.45 (d, J=9.0 Hz, 1H), 4.20 (d, J=9.0 Hz, 1H),2.07-1.98 (m, J=8.0 Hz, 1H), 1.83-1.69 (m, 2H), 1.59 (s, 3H), 1.56 (s,9H), 0.99 (dd, J=8.0, 6.5 Hz, 6H).

Part F: (S)-tert-butyl(1-(4-bromo-2-formylphenoxy)-2,4-dimethylpentan-2-yl)carbamate

To a 20 mL vial was added 5-bromo-2-hydroxybenzaldehyde (81 mg, 0.403mmol), (S)-tert-butyl4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(107.4 mg, 0.366 mmol), and K₂CO₃ (152 mg, 1.098 mmol) in DMF (1.2 mL)to give a white suspension. The vial was sealed and the mixture washeated at 80° C. for 17 h. The reaction mixture was cooled to rt andpartitioned between water and EtOAc. The layers were separated. Theorganic layer was washed with water, brine, dried (Na₂SO₄) andconcentrated under reduced pressure. The crude residue was purified bysilica gel chromatography (up to 40% EtOAc/hexanes) to afford(S)-tert-butyl(1-(4-bromo-2-formylphenoxy)-2,4-dimethylpentan-2-yl)carbamate (115 mg,0.278 mmol, 76%) as a colorless oil. ¹H NMR (400 MHz, Chloroform-d) δ10.43 (s, 1H), 7.89 (d, J=2.6 Hz, 1H), 7.59 (dd, J=8.9, 2.6 Hz, 1H),6.93 (d, J=8.8 Hz, 1H), 4.58 (s, 1H), 4.29 (d, J=8.8 Hz, 1H), 4.09 (d,J=8.8 Hz, 1H), 1.94-1.74 (m, 2H), 1.48 (dd, J=13.9, 4.8 Hz, 1H), 1.39(s, 3H), 1.37 (s, 9H), 0.98 (dd, J=6.6, 4.8 Hz, 6H); (ESI) m/e 314.0,316.0 Br pattern [(M-Boc+H)⁺, calcd C₁₄H₂₁BrNO₂, 414.1]; LC/MS retentiontime (method B): t_(R)=2.39 min.

Part G: (S)-methyl(4-(4-((2-Boc-amino-2,4-dimethylpentyl)oxy)-3-carbonylphenyl)pyridin-2-yl)carbamate

To a 2 mL vial was added (S)-tert-butyl(1-(4-bromo-2-formylphenoxy)-2,4-dimethylpentan-2-yl)carbamate (27.9 mg,0.067 mmol), (2-((methoxycarbonyl)amino)pyridin-4-yl)boronic acid (19.79mg, 0.101 mmol), and Na₂CO₃ (0.101 mL, 0.202 mmol) in dioxane (0.5 mL)under nitrogen to give a colorless suspension.1,1′-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride, toluene(2.77 mg, 3.37 μmol) was added under nitrogen. The vial was sealed andheated at 100° C. (bath temp: 105° C.) for 3 h. LCMS showed conversionto the desired product (M+H=486), but with some starting material left.A bit more reagents was added and heating continued for another 3 h.LCMS showed no more starting material. The mixture was diluted withEtOAc and passed through a plug of Na₂SO₄. The organic solution wasconcentrated. Obtained (S)-methyl(4-(4-((2-Boc-amino-2,4-dimethylpentyl)oxy)-3-carbonylphenyl)pyridin-2-yl)carbamateas a tan residue which was carried on without further purification. LCMS(ESI) m/e 486.4 [(M+H)⁺, calcd C₂₆H₃₆N₃O₆, 486.3]; LC/MS retention time(method C): t_(R)=4.23 min.

Part H: (S)-methyl(4-(4-((2-Boc-amino-2,4-dimethylpentyl)oxy)-3-(hydroxymethyl)phenyl)pyridin-2-yl)carbamate

To a 2 mL vial was added crude aldehyde (10.68 mg, 0.022 mmol) in MeOH(0.5 mL) to give a tan solution. NaBH₄ (5 mg, 0.132 mmol) was added. Themixture was stirred at rt for 1 h. The mixture was partitioned betweenwater and EtOAc. The layers were separated. The organic layer was washedwith brine, dried (Na₂SO₄) and concentrated under reduced pressure. Thetan residue was directly carried onto next reaction. LCMS (ESI) m/e488.2 [(M+H)⁺, calcd C₂₆H₃₈N₃O₆, 488.3]; LC/MS retention time (methodB): t_(R)=2.00 min.

Part I: (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(hydroxymethyl)phenyl)pyridin-2-yl)carbamate

To a 25 mL flask was added (S)-methyl(4-(4-((2-Boc-amino-2,4-dimethylpentyl)oxy)-3-(hydroxymethyl)phenyl)pyridin-2-yl)carbamate(10.73 mg, 0.022 mmol) in CH₂Cl₂ (1 mL) to give a tan solution. TFA (0.5ml, 6.49 mmol) was added under nitrogen. The mixture was stirred at rtfor 1 h. The mixture was concentrated. The residue was dissolved inMeOH, filtered, and purified by reverse phase HPLC(acetonitrile/water/10 mM ammonium acetate) to afford (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(hydroxymethyl)phenyl)pyridin-2-yl)carbamate(7.6 mg, 0.019 mmol, 86% yield for three steps) as a colorless solid. ¹HNMR (500 MHz, DMSO-d₆) δ 8.28 (d, J=5.2 Hz, 1H), 8.12 (s, 1H), 7.77 (d,J=2.4 Hz, 1H), 7.61 (dd, J=8.6, 2.4 Hz, 1H), 7.32 (d, J=5.2 Hz, 1H),7.06 (d, J=8.5 Hz, 1H), 4.63 (s, 2H), 3.77 (s, 2H), 3.70 (s, 3H), 1.79(td, J=11.7, 10.6, 5.5 Hz, 1H), 1.42 (qd, J=14.0, 5.6 Hz, 2H), 1.14 (s,3H), 0.93 (t, J=7.2 Hz, 6H); LCMS (ESI) m/e 388.1 [(M+H)⁺, calcdC₂₁H₃₀N₃O₄, 388.2]; LC/MS retention time (method B): t_(R)=1.55 min.

Example 33 (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyclopropylphenyl)pyridin-2-yl)carbamate

Prepared as described in Example 32.

Part A: (S)-tert-butyl(1-(4-bromo-2-cyclopropylphenoxy)-2,4-dimethylpentan-2-yl)carbamate

To a 100 mL round-bottomed flask was added 2-cyclopropylphenol (584 mg,4.35 mmol) in CH₂Cl₂ (22 mL) to give a colorless solution. Br₂ (0.224mL, 4.35 mmol) was added dropwise at 0° C. The mixture was stirred at 0°C. for 1 h. The mixture was concentrated under reduced pressure toafford (S)-tert-butyl(1-(4-bromo-2-cyclopropylphenoxy)-2,4-dimethylpentan-2-yl)carbamate (992mg, 4.35 mmol, 100% yield) as a colorless oil. ¹H NMR (400 MHz,Chloroform-d) δ 7.24 (dd, J=8.6, 2.5 Hz, 1H), 7.20 (dd, J=2.5, 0.9 Hz,1H), 6.76 (d, J=8.5 Hz, 1H), 5.43 (s, 1H), 1.82 (tt, J=8.3, 5.3 Hz, 1H),1.04-0.97 (m, 2H), 0.70-0.64 (m, 2H); LC/MS retention time (method B):t_(R)=2.09 min.

Part B: (S)-tert-butyl(1-(4-bromo-2-cyclopropylphenoxy)-2,4-dimethylpentan-2-yl)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 7.21 (dd, J=8.7, 2.5 Hz, 1H), 6.98 (d,J=2.5 Hz, 1H), 6.71 (d, J=8.7 Hz, 1H), 4.67 (s, 1H), 4.10 (d, J=9.0 Hz,1H), 3.94 (d, J=8.8 Hz, 1H), 2.16-2.08 (m, 1H), 1.84 (ddt, J=13.0, 10.9,6.5 Hz, 2H), 1.69-1.59 (m, 1H), 1.43 (s, 3H), 1.42 (s, 9H), 0.99 (dd,J=6.5, 3.1 Hz, 6H), 0.97-0.92 (m, 2H), 0.68-0.61 (m, 2H); LCMS (ESI) m/e447.9 [(M+Na)⁺, calcd C₂₁H₃₂Br₁N₁Na₁O₃, 448.2]; LC/MS retention time(method B): t_(R)=2.59 min.

Part C: (S)-methyl(4-(4-((2-Boc-amino-2,4-dimethylpentyl)oxy)-3-cyclopropylphenyl)pyridin-2-yl)carbamate

LCMS (ESI) m/e 498.1 [(M+H)⁺, calcd C₂₈H₄₀N₃O₅, 498.3]; LC/MS retentiontime (method B): t_(R)=2.24 min.

Part D: (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyclopropylphenyl)pyridin-2-yl)carbamate

¹H NMR (500 MHz, DMSO-d₆) δ 8.25 (d, J=5.3 Hz, 1H), 8.05 (s, 1H), 7.50(dd, J=8.5, 2.4 Hz, 1H), 7.32 (d, J=5.4 Hz, 1H), 7.19 (d, J=2.3 Hz, 1H),7.04 (d, J=8.5 Hz, 1H), 3.81-3.73 (m, 2H), 3.70 (s, 3H), 2.20 (ddd,J=13.9, 8.8, 5.4 Hz, 1H), 1.82 (dt, J=12.8, 6.3 Hz, 1H), 1.49-1.38 (m,2H), 1.16 (s, 3H), 0.94 (q, J=6.2 Hz, 8H), 0.72 (q, J=5.1 Hz, 2H); LCMS(ESI) m/e 398.1 [(M+H)⁺, calcd C₂₃H₃₂N₃O₃, 398.2]; LC/MS retention time(method B): t_(R)=1.73 min.

Example 34(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-5-(hydroxymethyl)pyridin-2-yl)acetamide

Prepared as described in Example 19.

Part A: N-(4-chloro-5-(hydroxymethyl)pyridin-2-yl)acetamide

To a 25 mL vial was added (4,6-dichloropyridin-3-yl)methanol (125.8 mg,0.707 mmol), and acetamide (62.6 mg, 1.060 mmol) in 1,4-dioxane (4 mL)to give a colorless solution. While degassing with N₂, PdOAc₂ (7.93 mg,0.035 mmol), XANTPHOS (30.7 mg, 0.053 mmol), Cs₂CO₃ (368 mg, 1.131 mmol)were added. The vial was sealed under nitrogen and heated at 110° C.(bath: 112° C.) for 22 h (1:30 pm). The reaction mixture was cooled tort and partitioned between water and EtOAc. There were some insolublesolids which were removed by filtration. The layers were separated. Theaqueous layer was extracted 4 times with EtOAc (there were still productleft in aq.). The combined organic layers were washed with brine, driedand concentrated. The residue was purified by silica gel chromatography(up to 10% MeOH/CH₂Cl₂) to affordN-(4-chloro-5-(hydroxymethyl)pyridin-2-yl)acetamide (90 mg, o.449 mmol,64% yield) as a white solid: ¹H NMR (400 MHz, Methanol-d₄) δ 8.34 (s,1H), 8.19 (s, 1H), 4.69 (s, 2H), 2.19 (s, 3H); LCMS (ESI) m/e 201.1[(M+H)⁺, calcd C₈H₁₀ClN₂O₂, 201.1]; LC/MS retention time (method B):t_(R)=1.73 min.

Part B: (2-acetamido-5-(hydroxymethyl)pyridin-4-yl)boronic acid

To a 20 mL vial was addedN-(4-chloro-5-(hydroxymethyl)pyridin-2-yl)acetamide (48 mg, 0.239 mmol),hypodiboric acid (32.2 mg, 0.359 mmol),2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (2.281 mg, 4.79μmol), Xphos precatalyst (1.882 mg, 2.393 μmol) and potassium acetate(70.4 mg, 0.718 mmol) in ethanol (2.2 mL) to give a tan suspension(degassed with N₂ before adding reagents). The bottle was capped andheated at 80° C. for 1.5 h. The mixture was cooled to rt andconcentrated under reduced pressure. The crude material was carried onwithout purification.

Part C:(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-5-(hydroxymethyl)pyridin-2-yl)acetamide

To a 20 mL vial was added(2-acetamido-5-(hydroxymethyl)pyridin-4-yl)boronic acid (50.2 mg, 0.239mmol) was added potassium phosphate tribasic (2 mL, 1.000 mmol). Afterdegassing with N₂ for 5 min, Xphos precatalyst (3.76 mg, 4.78 μmol) and(S)-1-(4-bromo-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(30 mg, 0.076 mmol) (prepared as described in Example 19. Part A) intetrahydrofuran (2 mL) were added. The vial was sealed and heated at 80°C. for 18 h. The reaction mixture was cooled to rt and the volatileswere removed under reduced pressure. The residue was partitioned betweenwater and EtOAc. The organic layer was dried, filtered and concentrated.The residue was dissolved in MeOH and purified by reverse phase HPLC(acetonitrile/water/10 mM ammonium acetate) to afford(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-5-(hydroxymethyl)pyridin-2-yl)acetamide(27.7 mg, 0.060 mmol, 79% yield) as an off-white solid. ¹H NMR (600 MHz,DMSO-d₆) δ 10.57 (s, 1H), 8.38 (s, 1H), 8.02 (s, 1H), 7.80 (s, 1H),7.78-7.71 (m, 1H), 7.35 (d, J=8.6 Hz, 1H), 4.36 (s, 2H), 3.86 (q, J=8.8Hz, 2H), 2.10 (s, 3H), 1.81 (dt, J=12.6, 6.1 Hz, 1H), 1.45-1.37 (m, 2H),1.13 (s, 3H), 0.92 (dd, J=6.6, 3.4 Hz, 6H); LCMS (ESI) m/e 440.2[(M+H)⁺, calcd C₂₂H₂₉F₃N₃O₃, 440.2]; LC/MS retention time (method B):t_(R)=1.67 min.

Example 35(S)-1-(4-(2-(difluoromethyl)pyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 19. Obtained(S)-1-(4-(2-(difluoromethyl)pyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(25.5 mg, 0.062 mmol, 54% yield) as an off-white solid. ¹H NMR (600 MHz,DMSO-d₆) δ 8.74 (d, J=5.1 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.11 (s, 1H),8.06 (s, 1H), 7.96 (d, J=5.1 Hz, 1H), 7.44 (d, J=8.7 Hz, 1H), 7.01 (t,J=54.9 Hz, 1H), 4.05 (q, J=9.6 Hz, 2H), 1.81 (dt, J=12.9, 6.6 Hz, 1H),1.61-1.47 (m, 2H), 1.25 (s, 3H), 0.92 (t, J=6.9 Hz, 6H); LCMS (ESI) m/e403.4 [(M+H)⁺, calcd C₂H₂₄F₅N₂O₁, 403.2]; LC/MS retention time (methodA): t_(R)=2.13 min.

Example 36(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-(difluoromethyl)pyridin-4-yl)benzonitrile

Prepared as described in Example 19. Obtained(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-(difluoromethyl)pyridin-4-yl)benzonitrile(32 mg, 0.086 mmol, 60% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.48 (d, J=5.2 Hz, 1H), 8.11 (d, J=2.5 Hz, 1H), 7.95 (dd,J=9.0, 2.4 Hz, 1H), 7.80 (s, 1H), 7.69 (d, J=5.2 Hz, 1H), 7.14 (d, J=8.9Hz, 1H), 6.73 (t, J=54.8 Hz, 1H), 3.80-3.68 (m, 2H), 1.56 (dp, J=12.5,6.4 Hz, 1H), 1.23 (qd, J=14.0, 5.5 Hz, 2H), 0.95 (s, 3H), 0.68 (dd,J=6.7, 4.7 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d6) δ −115.30 (d, J=54.0 Hz);LCMS (ESI) m/e 360.2 [(M+H)⁺, calcd C₂₀H₂₄F₂N₃O₁, 360.2]; LC/MSretention time (method B): t_(R)=1.69 min.

Example 37(S)-1-(2-(difluoromethyl)-4-(2-(difluoromethyl)pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 19. Obtained(S)-1-(2-(difluoromethyl)-4-(2-(difluoromethyl)pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine(31.9 mg, 0.080 mmol, 61% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.48 (d, J=5.1 Hz, 1H), 7.81 (dd, J=8.9, 2.4 Hz, 1H), 7.76(d, J=3.6 Hz, 2H), 7.67 (d, J=5.1 Hz, 1H), 7.22-6.94 (m, 2H), 6.76 (t,J=54.9 Hz, 1H), 3.68 (d, J=2.2 Hz, 2H), 1.54 (dp, J=12.7, 6.3 Hz, 1H),1.30-1.13 (m, 2H), 0.95 (s, 3H), 0.67 (dd, J=15.9, 6.6 Hz, 6H); ¹⁹F NMR(376 MHz, DMSO-d6) δ −73.65, −115.33; LCMS (ESI) m/e 407.2 [(M+Na)⁺,calcd C₂₀H₂₄F₄N₂Na₁O₁, 407.2]; LC/MS retention time (method B):t_(R)=1.89 min.

Example 38(S)-1-(4-(2-(difluoromethyl)pyridin-4-yl)-2-(trifluoromethoxy)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 19. Obtained(S)-1-(4-(2-(difluoromethyl)pyridin-4-yl)-2-(trifluoromethoxy)phenoxy)-2,4-dimethylpentan-2-amine(21.1 mg, 0.050 mmol, 39% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.55 (d, J=5.2 Hz, 1H), 7.85 (s, 1H), 7.78 (dd, J=13.4, 5.4Hz, 3H), 7.22 (d, J=8.6 Hz, 1H), 6.83 (t, J=54.9 Hz, 1H), 3.71 (d, J=3.6Hz, 2H), 1.64 (dt, J=12.7, 6.3 Hz, 1H), 1.26 (dq, J=14.8, 8.3, 6.9 Hz,2H), 0.98 (s, 3H), 0.75 (t, J=5.9 Hz, 6H); LCMS (ESI) m/e 419.3 [(M+H)⁺,calcd C₂₀H₂₄F₅N₂O₂, 419.2]; LC/MS retention time (method B): t_(R)=2.03min.

Example 39(S)-1-(4-(3-chloro-2-fluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 19. Obtained(S)-1-(4-(3-chloro-2-fluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(14 mg, 0.035 mmol, 42% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.25 (d, J=5.1 Hz, 1H), 7.88-7.79 (m, 2H), 7.53 (d, J=5.1 Hz,1H), 7.40 (d, J=8.5 Hz, 1H), 3.87 (q, J=8.9 Hz, 2H), 1.80 (hept, J=6.5Hz, 1H), 1.39 (d, J=5.6 Hz, 2H), 1.12 (s, 3H), 0.92 (dd, J=6.7, 2.4 Hz,6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −61.18, −71.35; LCMS (ESI) m/e 405.1[(M+H)⁺, calcd C₁₉H₂₂Cl₁F₄N₂O₁, 405.1]; LC/MS retention time (method B):t_(R)=2.04 min.

Example 40(S)-1-(4-(5-chloro-2-fluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 19. Obtained(S)-1-(4-(5-chloro-2-fluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(15.2 mg, 0.037 mmol, 43% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.45 (s, 1H), 7.88-7.80 (m, 2H), 7.46 (d, J=1.9 Hz, 1H), 7.39(d, J=8.5 Hz, 1H), 3.93-3.82 (m, 2H), 1.80 (dp, J=12.8, 6.5 Hz, 1H),1.40 (d, J=5.5 Hz, 2H), 1.13 (s, 3H), 0.92 (dd, J=6.6, 2.5 Hz, 6H); ¹⁹FNMR (376 MHz, DMSO-d6) δ −61.16, −71.37; LCMS (ESI) m/e 405.1 [(M+H)⁺,calcd C₁₉H₂₂Cl₁F₄N₂O₁, 405.1]; LC/MS retention time (method B):t_(R)=2.04 min.

Example 41(S)-1-(4-(2-fluoro-3-methylpyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 19. Obtained(S)-1-(4-(2-fluoro-3-methylpyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(14.1 mg, 0.036 mmol, 42% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.10 (d, J=5.1 Hz, 1H), 7.72 (dd, J=8.6, 2.3 Hz, 1H), 7.67(d, J=2.2 Hz, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.29 (d, J=5.1 Hz, 1H), 3.87(q, J=8.8 Hz, 2H), 2.17 (s, 3H), 1.81 (dp, J=12.7, 6.4 Hz, 1H),1.46-1.35 (m, 2H), 1.13 (s, 3H), 0.92 (dd, J=6.7, 2.8 Hz, 6H); ¹⁹F NMR(376 MHz, DMSO-d6) δ −61.03, −71.80; LCMS (ESI) m/e 385.2 [(M+H)⁺, calcdC₂H₂₅F₄N₂O₁, 385.2]; LC/MS retention time (method B): t_(R)=1.99 min.

Example 42(S)-1-(4-(2,3-difluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 19. Obtained(S)-1-(4-(2,3-difluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(7 mg, 0.018 mmol, 21% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.10 (d, J=5.1 Hz, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.95 (d,J=2.3 Hz, 1H), 7.66 (t, J=5.1 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 3.90 (q,J=8.8 Hz, 2H), 1.79 (dq, J=12.8, 6.4 Hz, 1H), 1.40 (d, J=5.5 Hz, 2H),1.13 (s, 3H), 0.92 (dd, J=6.6, 2.2 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d6) δ−61.23, −89.72, −89.79; LCMS (ESI) m/e 389.2 [(M+H)⁺, calcdC₁₉H₂₂F₅N₂O₁, 389.2]; LC/MS retention time (method B): t_(R)=2.01 min.

Example 43(S)-2,4-dimethyl-1-(4-(pyridin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine

Prepared as described in Example 19. A mixture of sodium carbonate(0.068mL, 0.136 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (3.89 mg, 4.76 μmol),pyridin-4-ylboronic acid (8.36 mg, 0.068 mmol) and(S)-1-(4-bromo-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(0.0241 g, 0.068 mmol) in dioxane (0.5 mL) (degassed with N₂) was heatedat 80° C. overnight. The reaction mixture was cooled to rt and dilutedwith ethyl acetate then washed with water (3×). The ethyl acetate layerwas dried (Na₂SO₄), filtered and concentrated under reduced pressure.The residue was purified by reverse phase HPLC (acetonitrile/water/10 mMammonium acetate). Obtained(S)-2,4-dimethyl-1-(4-(pyridin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine(89 mg, 0.088 mmol, 46% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.62 (d, J=5.9 Hz, 2H), 8.09 (d, J=9.2 Hz, 1H), 8.01 (s, 1H),7.75 (d, J=5.5 Hz, 2H), 7.37 (d, J=8.8 Hz, 1H), 3.87 (d, J=7.0 Hz, 2H),1.84-1.74 (m, 1H), 1.39 (d, J=5.5 Hz, 2H), 1.12 (s, 3H), 0.91 (d, J=6.6Hz, 6H) LCMS (ESI) m/e 353.2 [(M+H)⁺, calcd C₁₉H₂₄F₃N₂O, 353.2]; LC/MSretention time (method B): t_(R)=1.48 min.

Example 44(S)-1-(4-(2-fluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 43. Obtained(S)-1-(4-(2-fluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(9.3 mg, 0.025 mmol, 36% yield) as an off-white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 8.27 (d, J=5.4 Hz, 1H), 8.10-8.04 (m, 2H), 7.63 (d, J=5.4Hz, 1H), 7.45-7.39 (m, 2H), 4.19 (d, J=3.2 Hz, 2H), 1.94 (s, 3H), 1.77(d, J=5.6 Hz, 2H), 1.71-1.63 (m, 1H), 1.45 (s, 2H), 1.04 (d, J=6.6 Hz,3H), 1.02 (d, J=6.6 Hz, 3H); LCMS (ESI) m/e 371.2 [(M+H)⁺, calcdC₁₉H₂₃F₄N₂O, 371.2]; LC/MS retention time (method B): t_(R)=1.95 min.

Example 45(S)-2,4-dimethyl-1-(4-(2-methylpyridin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine

Prepared as described in Example 19. Obtained(S)-2,4-dimethyl-1-(4-(2-methylpyridin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine(16 mg, 0.044 mmol, 50% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.68 (d, J=5.8 Hz, 1H), 8.26 (dd, J=8.8, 2.6 Hz, 1H),8.19-8.18 (m, 1H), 8.04 (s, 1H), 7.94 (d, J=5.9 Hz, 1H), 7.51 (d, J=8.8Hz, 1H), 4.26 (q, J=10.1 Hz, 2H), 2.66 (s, 3H), 1.83 (dq, J=13.0, 6.5Hz, 1H), 1.74 (dd, J=14.3, 5.5 Hz, 1H), 1.62 (dd, J=14.6, 5.8 Hz, 1H),1.40 (s, 3H), 0.93 (dd, J=8.6, 6.4 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ−60.51, −73.76 (TFA); LCMS (ESI) m/e 367.2 [(M+H)⁺, calcd C₂₀H₂₆F₃N₂O₁,367.2]; LC/MS retention time (method B): t_(R)=1.51 min.

Example 46(S)-1-(4-(3-methoxypyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 19. Obtained(S)-1-(4-(3-methoxypyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(8.5 mg, 0.021 mmol, 24% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.47 (s, 1H), 8.28 (d, J=4.8 Hz, 1H), 7.85 (d, J=9.0 Hz, 1H),7.82 (d, J=2.3 Hz, 1H), 7.41 (d, J=4.8 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H),3.91 (s, 3H), 3.86 (q, J=8.9 Hz, 2H), 1.80 (hept, J=6.4 Hz, 1H), 1.40(d, J=5.5 Hz, 2H), 1.13 (s, 3H), 0.92 (dd, J=6.8, 2.5 Hz, 6H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ −61.00; LCMS (ESI) m/e 383.2 [(M+H)⁺, calcdC₂₀H₂₆F₃N₂O₂, 383.2]; LC/MS retention time (method B): t_(R)=1.58 min.

Example 47(S)-1-(4-(3-fluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 19. Obtained(S)-1-(4-(3-fluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amin(8.9 mg, 0.023 mmol, 25% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.66 (d, J=2.6 Hz, 1H), 8.51 (d, J=4.9 Hz, 1H), 7.96 (d,J=8.8 Hz, 1H), 7.91 (d, J=2.3 Hz, 1H), 7.70 (dd, J=7.1, 4.9 Hz, 1H),7.41 (d, J=8.7 Hz, 1H), 3.89 (q, J=8.9 Hz, 2H), 1.80 (dp, J=12.7, 6.4Hz, 1H), 1.40 (d, J=5.5 Hz, 2H), 1.13 (s, 3H), 0.92 (dd, J=6.6, 2.3 Hz,6H); ¹⁹F NMR (376 MHz, DMSO-d6) δ −61.17, −133.88; LCMS (ESI) m/e 371.2[(M+H)⁺, calcd C₁₉H₂₃F₄N₂O₁, 371.2]; LC/MS retention time (method B):t_(R)=1.88 min.

Example 48(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-methylpyridin-4-yl)benzonitrile

Prepared as described in Example 19. Obtained(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-methylpyridin-4-yl)benzonitrile(39.4 mg, 0.116 mmol, 80% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.49 (d, J=5.2 Hz, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.11 (dd,J=8.9, 2.4 Hz, 1H), 7.64 (s, 1H), 7.54 (dd, J=5.3, 1.9 Hz, 1H), 7.36 (d,J=8.9 Hz, 1H), 3.98-3.87 (m, 2H), 3.58 (s, 2H), 2.52 (s, 3H), 1.82 (dt,J=12.8, 6.4 Hz, 1H), 1.50-1.37 (m, 2H), 1.16 (s, 3H), 0.93 (dd, J=6.6,3.9 Hz, 6H); LCMS (ESI) m/e 324.1 [(M+H)⁺, calcd C₂₀H₂₆N₃O₁, 324.2];LC/MS retention time (method B): t_(R)=1.46 min.

Example 49(S)-1-(2-cyclopropyl-4-(2-methylpyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 19. Obtained(S)-1-(2-cyclopropyl-4-(2-methylpyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine(13.8 mg, 0.040 mmol, 41% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.42 (d, J=5.3 Hz, 1H), 7.56 (dd, J=8.4, 2.3 Hz, 1H), 7.53(s, 1H), 7.44 (d, J=5.3 Hz, 1H), 7.25 (d, J=2.3 Hz, 1H), 7.02 (d, J=8.5Hz, 1H), 3.77 (d, J=2.2 Hz, 2H), 2.22 (ddd, J=13.9, 8.4, 5.3 Hz, 1H),1.82 (dq, J=12.7, 6.4 Hz, 1H), 1.52-1.39 (m, 2H), 1.17 (s, 3H), 0.93 (t,J=6.5 Hz, 8H), 0.77 (q, J=4.3, 3.5 Hz, 2H). (2-Py-Me was likely buriedin DMSO peak of 2.51); LCMS (ESI) m/e 339.1 [(M+H)⁺, calcd C₂₂H₃₁N₂O₁,339.2]; LC/MS retention time (method B): t_(R)=1.56 min.

Example 50(S)-1-(2-(difluoromethyl)-4-(2-methylpyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 19. Obtained(S)-1-(2-(difluoromethyl)-4-(2-methylpyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine(22 mg, 0.061 mmol, 69% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.48 (d, J=5.3 Hz, 1H), 7.96 (d, J=8.9 Hz, 1H), 7.92 (d,J=2.4 Hz, 1H), 7.60 (s, 1H), 7.54-7.47 (m, 1H), 7.43-7.16 (m, 2H), 3.87(s, 2H), 2.53 (s, 3H), 1.80 (dt, J=12.8, 6.4 Hz, 1H), 1.43 (qd, J=14.1,5.7 Hz, 2H), 1.16 (s, 3H), 0.94 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.7 Hz,3H); LCMS (ESI) m/e 349.0 [(M+H)⁺, calcd C₂₀H₂₇F₂N₂O₁, 349.2]; LC/MSretention time (method B): t_(R)=1.47 min.

Example 51 methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-[3,4′-bipyridin]-2′-yl)carbamate

Prepared as described in Example 29.

Part A: Benzyl(1-((5-chloropyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

An NMP (0.3 mL) suspension of 5-chloropyridin-2-ol (0.023 g, 0.180mmol), sodium carbonate (0.019 g, 0.180 mmol) and benzyl4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(0.0392 g, 0.120 mmol) was heated to 80° C. overnight. The reactionmixture was cooled to rt and diluted with ethyl acetate and washed withwater (3×). The ethyl acetate layer was separated, dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue waspurified via silica gel chromatography (0-30% ethyl acetate in hexanes)to afford benzyl(1-((5-chloropyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (0.0387g, 0.103 mmol, 86% yield) as an off-white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.08 (d, J=2.3 Hz, 1H), 7.54 (dd, J=8.8, 2.8 Hz, 1H),7.37-7.32 (m, 5H), 6.71 (d, J=8.8 Hz, 1H), 5.06 (s, 3H), 4.42 (d, J=10.5Hz, 1H), 4.26 (d, J=10.8 Hz, 1H), 1.87-1.74 (m, 2H), 1.72-1.63 (m, 1H),1.43 (s, 3H), 0.96 (dd, J=6.3, 4.8 Hz, 6H); LCMS (ESI) m/e 377.3[(M+H)⁺, calcd C₂₀H₂₆ClN₂O₃, 377.2]; LC/MS retention time (method A):t_(R)=2.42 min.

Part B: Cbz methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-[3,4′-bipyridin]-2′-yl)carbamate

A mixture of 2^(nd) generation XPHOS precatalyst (1.587 mg, 2.017 μmol),potassium phosphate tribasic (0.403 mL, 0.202 mmol),(2-((methoxycarbonyl)amino)pyridin-4-yl)boronic acid (0.020 g, 0.101mmol) and benzyl(1-((5-chloropyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (0.038g, 0.101 mmol) in THE (0.2 mL) was degassed via vacuum/N₂ fill cyclethree times. The reaction mixture was heated at 70° C. overnight. Thereaction was cooled to rt and diluted with ethyl acetate and washed withwater (2×) followed by brine. The ethyl acetate layer was separated,dried (Na₂SO₄), filtered and concentrated. The product was purifiedsilica gel chromatography (50-100% ethyl acetate in hexanes) to affordCbz methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-[3,4′-bipyridin]-2′-yl)carbamate(0.011. g, 0.022 mmol, 22% yield) as a white solid. LCMS (ESI) m/e 493.3[(M+H)⁺, calcd C₂₇H₃₃N₄O₅, 493.3]; LC/MS retention time (method B):t_(R)=2.13 min.

Part C: methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-[3,4′-bipyridin]-2′-yl)carbamate

A mixture of Pd/C (5 mg, 4.70 μmol) and Cbz methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-[3,4′-bipyridin]-2′-yl)carbamate(0.011 g, 0.022 mmol) in ethanol (4 mL) was hydrogenated with a H₂balloon at room temperature overnight. The reaction was filtered andwashed with DCM. The filtrate was concentrated under reduced pressureand the residue was purified via reverse phase HPLC(acetonitrile/water/10 mM ammonium acetate) to afford methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-[3,4′-bipyridin]-2′-yl)carbamate(6.6 mg, 0.018 mmol, 82% yield) as an off-white solid. ¹H NMR (600 MHz,DMSO-d₆) δ 8.53 (s, 1H), 8.32 (d, J=5.1 Hz, 1H), 8.08 (s, 1H), 8.06 (dd,J=8.6, 2.0 Hz, 1H), 7.38 (d, J=5.1 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H),4.14-4.00 (m, 2H), 3.70 (s, 3H), 1.89 (s, 3H), 1.80 (dt, J=12.7, 6.1 Hz,1H), 1.47-1.33 (m, 2H), 0.93 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H);LCMS (ESI) m/e 359.3 [(M+H)⁺, calcd C₁₉H₂₇N₄O₃, 359.2]; LC/MS retentiontime (method B): t_(R)=1.55 min.

Example 52(S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-methyl-[3,4′-bipyridin]-2′-yl)carbamate

PREPARED as in Example 51.

Part A:(S)-1-((5-bromo-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

LCMS (ESI) m/e 323.1 [(M+Na)⁺, calcd C₁₃H₂₁BrN₂ONa, 323.1]; LC/MSretention time (method B): t_(R)=1.96 min.

Part B: (S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-methyl-[3,4′-bipyridin]-2′-yl)carbamate

A mixture of sodium carbonate (0.149 mL, 0.299 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (6.10 mg, 7.47 μmol),(S)-1-((5-bromo-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(0.045 g, 0.149 mmol) and(2-((methoxycarbonyl)amino)pyridin-4-yl)boronic acid (0.029 g, 0.149mmol) in dioxane (0.5 mL) (degassed with N₂) was heated at 80° C. for 5h. The reaction was diluted with ethyl acetate and washed with water(3×). The ethyl acetate layer was dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The residue was purified by reversephase HPLC (acetonitrile/water/10 mM ammonium acetate to afford(S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-methyl-[3,4′-bipyridin]-2′-yl)carbamate(11.0 mg, 0.073 mmol, 20% yield) as an off-white solid. ¹H NMR (600 MHz,DMSO-d₆) δ 10.25 (br. s., 1H), 8.35 (s, 1H), 8.31 (d, J=5.1 Hz, 1H),8.08 (s, 1H), 7.91 (s, 1H), 7.36 (d, J=5.1 Hz, 1H), 4.20-4.09 (m, 2H),2.51 (br. s., 3H), 2.29 (s, 3H), 1.86-1.77 (m, 1H), 1.59-1.39 (m, 2H),1.20 (d, J=5.1 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H);LCMS (ESI) m/e 373.4 [(M+H)⁺, calcd C₂₀H₂₉N₄O3 373.2]; LC/MS retentiontime (method A): t_(R)=1.89 min.

Example 53(S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-cyano-[3,4′-bipyridin]-2′-yl)carbamate

Prepared as in Example 51.

Part A: (S)-tert-butyl(1-((5-bromo-3-cyanopyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

A mixture of sodium carbonate (0.246 g, 2.323 mmol), (S)-tert-butyl4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(0.3408 g, 1.162 mmol) and 5-bromo-2-hydroxynicotinonitrile (0.277 g,1.394 mmol) in DMF (4 mL) was heated at 80° C. overnight. The reactionwas cooled to rt and diluted with ethyl acetate then washed with NaOH(1N) (2×) and water (1×). The ethyl acetate layer was separated, dried(Na₂SO₄), filtered and concentrated under reduced pressure. The productwas purified silica gel chromatography (0-25% ethyl acetate in hexanes)to afford (S)-tert-butyl(1-((5-bromo-3-cyanopyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(0.261 g, 0.633 mmol, 55% yield) as a clear oil. LCMS (ESI) m/e 436.1[(M+Na)⁺, calcd C₁₈H₂₆BrN₃O₃Na, 436.1]; LC/MS retention time (method B):t_(R)=2.38 min.

Part B: Boc-(S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-cyano-[3,4′-bipyridin]-2′-yl)carbamate

LCMS (ESI) m/e 484.4 [(M+H)⁺, calcd C₂₅H₃₄N₅O₅, 484.3]; LC/MS retentiontime (method A): t_(R)=2.24 min.

Part C:(S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-cyano-[3,4′-bipyridin]-2′-yl)carbamate

Obtained(S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-cyano-[3,4′-bipyridin]-2′-yl)carbamate(13.3 mg, 0.034 mmol, 36% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.36 (s, 1H), 8.81-8.77 (m, 1H), 8.68-8.63 (m, 1H), 8.36 (d,J=5.1 Hz, 1H), 8.09 (s, 1H), 7.43 (d, J=4.0 Hz, 1H), 4.20 (d, J=5.9 Hz,2H), 3.71 (s, 3H), 3.39 (br. s., 2H), 1.82 (d, J=6.2 Hz, 1H), 1.40 (t,J=5.5 Hz, 2H), 1.14 (s, 3H), 0.95-0.90 (m, 6H); LCMS (ESI) m/e 367.2[(M-NH₂), calcd C₂₀H₂₃N₄O₃, 367.2]; LC/MS retention time (method B):t_(R)=1.63 min.

Example 54 (S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-4-methyl-[3,4′-bipyridin]-2′-yl)carbamate

Prepared as in Example 51.

Part A:(S)-1-((5-bromo-4-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

LCMS (ESI) m/e 301.2 [(M+H)⁺, calcd C₁₃H₂₂BrN₂O, 301.1]; LC/MS retentiontime (method A): t_(R)=1.77 min.

Part B: (S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-4-methyl-[3,4′-bipyridin]-2′-yl)carbamate

Obtained (S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-4-methyl-[3,4′-bipyridin]-2′-yl)carbamate(15.3 mg, 0.041 mmol, 32% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.34-8.30 (m, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 7.11-7.08 (m,1H), 6.85 (s, 1H), 4.01 (d, J=5.5 Hz, 2H), 3.68 (s, 3H), 2.26 (s, 3H),1.88 (s, 1H), 1.85-1.77 (m, 1H), 1.37 (s, 2H), 1.10 (s, 3H), 0.93 (m,6H); LCMS (ESI) m/e 373.3 [(M+H)⁺, calcd C₂₀H₂₉N₄O₃, 373.2]; LC/MSretention time (method B): t_(R)=1.60 min.

Example 55 (S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-chloro-[3,4′-bipyridin]-2′-yl)carbamate

Prepared as in Example 51.

Part A: (S)-tert-butyl(1-((5-bromo-3-chloropyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

¹H NMR (400 MHz, CHLOROFORM-d) δ 8.07 (d, J=2.3 Hz, 1H), 7.76 (d, J=2.3Hz, 1H), 4.65 (br. s., 1H), 4.48 (d, J=10.3 Hz, 1H), 4.32 (d, J=10.3 Hz,1H), 1.90-1.75 (m, 2H), 1.67-1.53 (m, 1H), 1.41 (s, 9H), 1.39 (s, 3H),0.99 (d, J=2.0 Hz, 3H), 0.97 (d, J=2.0 Hz, 3H); LCMS (ESI) m/e 443.1[(M+Na)⁺, calcd C₁₇H₂₆BrClN₂O₃Na, 443.1]; LC/MS retention time (methodB): t_(R)=2.55 min.

Part B: Boc-(S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-chloro-[3,4′-bipyridin]-2′-yl)carbamate

LCMS (ESI) m/e 493.4 [(M+H)⁺, calcd C₂₄H₃₄ClN₄O₅, 493.2]; LC/MSretention time (method A): t_(R)=2.38 min.

Part C: (S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-chloro-[3,4′-bipyridin]-2′-yl)carbamate

Obtained (S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-chloro-[3,4′-bipyridin]-2′-yl)carbamate(19.6mg, 0.047 mmol, 85% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.49 (d, J=2.2 Hz, 1H), 8.34 (d, J=5.1 Hz, 1H), 8.25 (d,J=2.2 Hz, 1H), 8.07 (s, 1H), 7.42 (dd, J=5.1, 1.5 Hz, 1H), 4.22-4.06 (m,2H), 3.71 (s, 3H), 1.87-1.75 (m, 1H), 1.48-1.34 (m, 2H), 1.14 (s, 3H),0.93 (d, J=3.7 Hz, 3H), 0.92 (d, J=3.7 Hz, 3H); LCMS (ESI) m/e 393.3[(M+H)⁺, calcd C₁₉H₂₆ClN₄O₃, 393.2]; LC/MS retention time (method A):t_(R)=1.98 min.

Example 56 (S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-methoxy-[3,4′-bipyridin]-2′-yl)carbamate

Prepared as in Example 51.

Part A:(S)-1-((5-bromo-3-methoxypyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

LCMS (ESI) m/e 338.9 [(M+Na)⁺, calcd C₁₃H₂₁BrN₂O₂Na, 339.1]; LC/MSretention time (method B): t_(R)=1.87 min.

Part B: (S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-methoxy-[3,4′-bipyridin]-2′-yl)carbamate

Obtained (S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-methoxy-[3,4′-bipyridin]-2′-yl)carbamate(8.4 mg, 0.021 mmol, 29% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.32 (d, J=5.1 Hz, 1H), 8.09 (s, 1H), 8.04 (d, J=1.8 Hz, 1H),7.56 (d, J=1.5 Hz, 1H), 7.41 (d, J=4.0 Hz, 1H), 4.08 (q, J=10.3 Hz, 2H),3.92 (s, 3H), 3.70 (s, 3H), 3.45 (br. s., 3H), 1.81 (dt, J=13.0, 6.3 Hz,1H), 1.47-1.31 (m, 2H), 1.12 (s, 3H), 0.92 (m, 6H); LCMS (ESI) m/e 389.1[(M+H)⁺, calcd C₂₀H₂₉N₄O₄, 389.2]; LC/MS retention time (method B):t_(R)=1.64 min.

Example 57(S)-1-((2′-chloro-5-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as in Example 51. Obtained(S)-1-((2′-chloro-5-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine(15 mg, 0.044 mmol, 49% yield) as an off-white solid. ¹H NMR (600 MHz,DMSO-d₆) δ 8.51 (br. s., 1H), 8.44 (d, J=5.1 Hz, 1H), 8.09 (br. s., 1H),7.87 (s, 1H), 7.76 (d, J=4.0 Hz, 1H), 4.10-4.04 (m, 2H), 2.26 (s, 3H),1.84-1.75 (m, 1H), 1.40 (t, J=6.2 Hz, 2H), 1.13 (s, 3H), 0.92 (t, J=6.4Hz, 6H); LCMS (ESI) m/e 334.3 [(M-NH₂)+, calcd C₁₈H₂₅ClN₃O, 334.2];LC/MS retention time (method B): t_(R)=1.94 min.

Example 58(S)-1-((2′-(difluoromethyl)-5-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as in Example 51. Obtained(S)-1-((2′-(difluoromethyl)-5-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine(15.1 mg, 0.043 mmol, 81% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.72 (d, J=5.2 Hz, 1H), 8.53 (d, J=2.5 Hz, 1H), 8.12 (d,J=2.5 Hz, 1H), 8.01 (s, 1H), 7.92 (d, J=5.2 Hz, 1H), 6.99 (t, J=54.9 Hz,1H), 4.16-4.02 (m, 2H), 2.28 (s, 3H), 1.80 (tt, J=11.5, 5.7 Hz, 1H),1.49-1.35 (m, 2H), 1.14 (s, 3H), 0.92 (m, 6H); LCMS (ESI) m/e 350.3[(M+H)⁺, calcd C₁₉H₂₆F₂N₃O, 350.2]; LC/MS retention time (method A):t_(R)=1.80 min.

Example 59(S)-6-((2-amino-2,4-dimethylpentyl)oxy)-2′-(difluoromethyl)-[3,4′-bipyridine]-5-carbonitrile

Prepared as in Example 51.

Part A: (S)-tert-butyl(1-((3-cyano-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

To a 20 mL vial was added (S)-tert-butyl(1-((5-bromo-3-cyanopyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(73 mg, 0.177 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (54.0 mg,0.212 mmol), and potassium acetate (52.1 mg, 0.531 mmol) in dioxane (2mL) with nitrogen bubbling to give a colorless suspension. PdCl₂(dppf)(3.89 mg, 5.31 μmol) was added under nitrogen. The vial was sealed andthe mixture was heated at 80° C. for 4 h. The reaction mixture wascooled to rt and concentrated under reduced pressure. The crude materialwas used directly in the next step.

Part B: (S)-tert-butyl(1-((5-cyano-2′-(difluoromethyl)-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

The mixture of (S)-tert-butyl(1-((3-cyano-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(0.040 g, 0.088 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloromethanecomplex (5.03 mg, 6.16 μmol), 4-chloro-2-(difluoromethyl)pyridinehydrochloride (0.018 g, 0.088 mmol) and Na₂CO₃ (0.176 mL, 0.352 mmol) indioxane (1 mL) (degassed with N₂) was heated at 120° C. for 16 h. Thereaction mixture was cooled to rt, diluted with ethyl acetate and washedwith water (3×). The ethyl acetate layer was dried (Na₂SO₄), filteredand concentrated under reduced pressure. The residue was directlycarried onto next reaction. LCMS (ESI) m/e 483.2 [(M+Na)⁺, calcdC₂₄H₃F₂N₄Na₁O₃, 483.2]; LC/MS retention time (method B): t_(R)=2.30 min.

Part C:(S)-6-((2-amino-2,4-dimethylpentyl)oxy)-2′-(difluoromethyl)-[3,4′-bipyridine]-5-carbonitrile

Prepared using procedure described in Example 51 to afford(S)-6-((2-amino-2,4-dimethylpentyl)oxy)-2′-(difluoromethyl)-[3,4′-bipyridine]-5-carbonitrile(4.7 mg, 0.013 mmol, 15% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 9.02 (d, J=2.5 Hz, 1H), 8.95 (d, J=2.6 Hz, 1H), 8.80 (d,J=5.1 Hz, 1H), 8.15 (s, 1H), 8.02 (d, J=5.0 Hz, 1H), 7.01 (t, J=54.8 Hz,1H), 4.63 (d, J=11.6 Hz, 1H), 4.51 (d, J=11.5 Hz, 1H), 1.86 (dq, J=12.4,6.2 Hz, 1H), 1.79 (dd, J=14.4, 5.5 Hz, 1H), 1.62 (dd, J=14.3, 5.5 Hz,1H), 1.41 (s, 3H), 0.98 (dd, J=6.7, 2.2 Hz, 6H); ¹⁹F NMR (376 MHz,DMSO-d6) δ −73.65; LCMS (ESI) m/e 383.3 [(M+Na)⁺, calcd C₁₉H₂₂F₂N₄Na₁O₁,383.2]; LC/MS retention time (method B): t_(R)=1.77 min.

Example 60(S)-1-((5-chloro-2′-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as in Example 51. Obtained(S)-1-((5-chloro-2′-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine(2 mg, 5.99 umol, 31% yield) as an off-white solid. H NMR (500 MHz,DMSO-d₆) δ 8.59 (d, J=1.8 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H), 8.39 (d,J=1.8 Hz, 1H), 7.67 (s, 1H), 7.57 (d, J=4.4 Hz, 1H), 4.19-4.10 (m, 2H),2.53 (s, 3H), 1.86-1.77 (m, 1H), 1.47-1.37 (m, 2H), 1.15 (s, 3H),0.99-0.88 (m, 6H); LCMS (ESI) m/e 334.3 [(M+H)⁺, calcd C₁₈H₂₅ClN₃O,334.2]; LC/MS retention time (method A): t_(R)=1.90 min.

Example 61(S)-1-((2′,5-dimethyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as in Example 51. Obtained(S)-1-((5-chloro-2′-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine(20.5 mg, 0.065 mmol, 41% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.47 (d, J=5.1 Hz, 1H), 8.43 (d, J=2.2 Hz, 1H), 8.01 (s, 1H),7.59 (s, 1H), 7.50 (d, J=5.5 Hz, 1H), 4.11-4.00 (m, 2H), 2.52 (s, 3H),2.26 (s, 3H), 1.80 (dq, J=12.6, 6.3 Hz, 1H), 1.46-1.35 (m, 2H), 1.13 (s,3H), 0.93 (d, J=4.8 Hz, 3H), 0.92 (d, J=4.8 Hz, 3H); LCMS (ESI) m/e297.1 [(M-NH₂)+, calcd C₁₉H₂₅ClN₂O, 297.2]; LC/MS retention time (methodB): t_(R)=1.51 min.

Example 62(S)-1-((5-methoxy-2′-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as in Example 51. Obtained(S)-1-((5-methoxy-2′-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine(20.5 mg, 0.065 mmol, 41% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.48 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 7.65 (d, J=4.0 Hz, 2H),7.55 (d, J=3.7 Hz, 1H), 4.06 (q, J=10.1 Hz, 2H), 3.93 (s, 3H), 2.53 (s,3H), 1.85-1.70 (m, 1H), 1.42-1.31 (m, 2H), 1.11 (s, 3H), 0.92 (t, J=7.0Hz, 6H); LCMS (ESI) m/e 330.1 [(M+H)⁺, calcd C₁₉H₂₈N₃O₂, 330.2]; LC/MSretention time (method B): t_(R)=1.42 min.

Example 63 methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-[2,4′-bipyridin]-2′-yl)carbamate

Prepared as in Example 29.

Part A: Benzyl(1-((5-chloropyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

LCMS (ESI) m/e 377.3 [(M+H)⁺, calcd C₂₀H₂₆ClN₂O₃, 377.2]; LC/MSretention time (method A): t_(R)=2.42 min.

Part B: Cbz methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-[2,4′-bipyridin]-2′-yl)carbamate

LCMS (ESI) m/e 493.0 [(M+H)⁺, calcd C₂₇H₃₃N₄O₅, 493.2]; LC/MS retentiontime (method B): t_(R)=2.15 min.

Part C: methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-[2,4′-bipyridin]-2′-yl)carbamate

A mixture of Pd/C (4 mg, 3.76 μmol) and Cbz protected methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-[2,4′-bipyridin]-2′-yl)carbamate(0.0123 g, 0.025 mmol) in ethanol (4 mL) was stirred under H₂ balloon atroom temperature overnight. The reaction mixture was filtered and theflask was rinsed with CH₂Cl₂. The filter cake was washed with CH₂Cl₂.The filtrate was concentrated under reduced pressure and the residue waspurified by reverse phase HPLC (acetonitrile/water/10 mM ammoniumacetate) to afford methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-[2,4′-bipyridin]-2′-yl)carbamate(12.1 mg, 0.032 mmol, 98% yield) as an off-white solid. ¹H NMR (600 MHz,DMSO-d₆) δ 10.14 (br. s., 1H), 8.49 (s, 1H), 8.45 (d, J=2.8 Hz, 1H),8.32 (d, J=5.1 Hz, 1H), 7.97 (d, J=8.8 Hz, 1H), 7.63 (d, J=5.1 Hz, 1H),7.54 (dd, J=8.7, 2.8 Hz, 1H), 3.84 (s, 2H), 3.71 (s, 3H), 1.82 (tt,J=12.7, 6.5 Hz, 1H), 1.46-1.35 (m, 2H), 1.14 (s, 3H), 0.95 (d, J=6.8 Hz,3H), 0.93 (d, J=6.6 Hz, 3H); LCMS (ESI) m/e 359.3 [(M+H)⁺, calcdC₁₉H₂₇N₄O₃, 359.2]; LC/MS retention time (method A): t_(R)=1.48 min.

Example 64 (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-6-methyl-[2,4′-bipyridin]-2′-yl)carbamate

Prepared as in Example 19.

Part A:(S)-1-((6-bromo-2-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

LCMS (ESI) m/e 284.2 [(M-NH₂), calcd C₁₃H₁₉BrNO, 284.1]; LC/MS retentiontime (method A): t_(R)=1.78 min (SM: t_(R)=1.61 min).

Part B: (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-6-methyl-[2,4′-bipyridin]-2′-yl)carbamate

Obtained (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-6-methyl-[2,4′-bipyridin]-2′-yl)carbamate(8.5 mg, 0.022 mmol, 34% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.48 (s, 1H), 8.30 (d, J=5.3 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H),7.67-7.60 (m, 1H), 7.43 (d, J=8.6 Hz, 1H), 3.79 (d, J=2.0 Hz, 2H), 3.58(s, 3H), 2.50 (s, 3H), 1.79 (m, 1H), 1.51-1.34 (m, 2H), 1.16 (s, 3H),0.93 (t, J=6.4 Hz, 6H); LCMS (ESI) m/e 373.3 [(M+H)⁺, calcd C₂₀H₂₉N₄O₃,373.2]; LC/MS retention time (method A): t_(R)=1.82 min.

Example 65(S)-1-((2′,6-dimethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as in Example 51. Obtained((S)-1-((2′,6-dimethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(7.2 mg, 0.022 mmol, 29% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.49 (d, J=5.3 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.87 (s, 1H),7.78 (d, J=5.3 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 3.78 (s, 2H), 2.54 (s,3H), 2.51 (s, 3H), 1.83 (dt, J=12.8, 6.4 Hz, 1H), 1.42 (t, J=5.2 Hz,2H), 1.15 (s, 3H), 0.94 (t, J=6.2 Hz, 6H); LCMS (ESI) m/e 314.4 [(M+H)⁺,calcd C₁₉H₂₈N₃O, 314.2]; LC/MS retention time (method A): t_(R)=1.84min.

Example 66 (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-6-chloro-[2,4′-bipyridin]-2′-yl)carbamate

Prepared as in Example 32.

Part A: (S)-tert-butyl(1-((2-chloro-6-iodopyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

LCMS (ESI) m/e 490.9 [(M+Na)⁺, calcd C₁₇H₂₆ClIN₂NaO₃, 491.1]; LC/MSretention time (method B): t_(R)=2.40 min.

Part B: (S)-methyl(5-((2-Boc-amino-2,4-dimethylpentyl)oxy)-6-chloro-[2,4′-bipyridin]-2′-yl)carbamate

LCMS (ESI) m/e 493.0 [(M+H)⁺, calcd C₂₄H₃₄ClN₄O₅, 493.2]; LC/MSretention time (method B): t_(R)=2.19 min.

Part C:(S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-6-chloro-[2,4′-bipyridin]-2′-yl)carbamate

Obtained(S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-6-chloro-[2,4′-bipyridin]-2′-yl)carbamate(12.6 mg, 0.032 mmol, 69% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.45 (s, 1H), 8.35 (d, J=5.3 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H),7.71 (d, J=8.4 Hz, 1H), 7.62 (d, J=5.2 Hz, 1H), 3.93 (s, 2H), 3.71 (s,3H), 1.81 (dq, J=13.1, 6.5 Hz, 1H), 1.45 (qd, J=14.0, 5.5 Hz, 2H), 1.18(s, 3H), 0.93 (t, J=6.4 Hz, 6H); LCMS (ESI) m/e 393.0 [(M+H)⁺, calcdC₁₉H₂₆Cl₁N₄O₃, 393.2]; LC/MS retention time (method A): t_(R)=1.66 min.

Example 67(S)-1-((6-chloro-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as in Example 32.

Part A: (S)-tert-butyl(1-((6-chloro-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Synthesis followed previous procedure. LCMS (ESI) m/e 434.0 [(M+H)⁺,calcd C₂₃H₃₃Cl₁N₃O₃, 434.2]; LC/MS retention time (method B): t_(R)=1.96min.

Part B:(S)-1-((6-chloro-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Obtained(S)-1-((6-chloro-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(4.6 mg, 0.013 mmol, 30% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.53 (d, J=5.2 Hz, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.85 (s, 1H),7.76 (d, J=5.3 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 3.91 (s, 2H), 2.55 (s,3H), 1.82 (p, J=6.4 Hz, 1H), 1.52-1.38 (m, 2H), 1.17 (s, 3H), 0.94 (t,J=6.3 Hz, 6H); LCMS (ESI) m/e 334.1 [(M+H)⁺, calcd C₁₈H₂₅Cl₁N₃O₁,334.2]; LC/MS retention time (method A): t_(R)=1.48 min.

Example 68(S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-methyl-[2,4′-bipyridin]-2′-yl)carbamate

Prepared as in Example 32.

Part A: (S)-tert-butyl(1-((6-chloro-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

LCMS (ESI) m/e 357.3 [(M+H)⁺, calcd CH₃₀ClN₂O₃, 357.2]; LC/MS retentiontime (method A): t_(R)=2.23 min.

Part B: (S)-tert-butyl(1-((6-chloro-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

LCMS (ESI) m/e 357.3 [(M+H)⁺, calcd CH₃₀ClN₂O₃, 357.2]; LC/MS retentiontime (method A): t_(R)=2.23 min.

Part C:(S)-1-((6-chloro-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

LCMS (ESI) m/e 257.0 [(M+H)⁺, calcd C₁₃H₂₂ClN₂O, 257.1]; LC/MS retentiontime (method B): t_(R)=1.70 min.

Part D: (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-methyl-[2,4′-bipyridin]-2′-yl)carbamate

Obtained (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-methyl-[2,4′-bipyridin]-2′-yl)carbamate(1.1 mg, 2.92 umol, 5% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.49 (s, 1H), 8.36 (s, 1H), 8.32 (d, J=5.1 Hz, 1H), 7.87 (s,1H), 7.63 (d, J=5.5 Hz, 1H), 3.89 (s, 2H), 3.71 (s, 3H), 2.32 (s, 3H),1.86-1.79 (m, 1H), 1.42 (t, J=5.7 Hz, 2H), 1.15 (s, 3H), 0.93 (t, J=6.6Hz, 6H); LCMS (ESI) m/e 373.1 [(M+H)⁺, calcd C₂₀H₂₉N₄O₃, 373.2]; LC/MSretention time (method B): t_(R)=1.67 min.

Example 69(S)-2,4-dimethyl-1-(4-(quinolin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine

Prepared as in Example 32. Obtained(S)-2,4-dimethyl-1-(4-(quinolin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine(50 mg, 0.123 mmol, 17% yield) as a brown solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.96 (d, J=4.5 Hz, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.87(dd, J=8.4, 0.9 Hz, 1H), 7.75 (td, J=4.2, 1.4 Hz, 2H), 7.65 (dd, J=8.5,2.0 Hz, 1H), 7.58-7.52 (m, 1H), 7.33 (d, J=4.5 Hz, 1H), 7.14 (d, J=8.5Hz, 1H), 3.93-3.86 (m, 2H), 1.82 (d, J=6.5 Hz, 1H), 1.68-1.59 (m, 2H),1.54 (t, J=5.5 Hz, 2H), 1.28 (s, 3H), 1.06-0.98 (m, 6H); ¹⁹F NMR (376MHz, CHLOROFORM-d) δ −62.29 (s, 3F); LCMS (ESI) m/e 403.2 [(M+H)⁺, calcdC₂₃H₂₆F₃N₂O, 403.2]; LC/MS retention time (method B): t_(R)=1.73 min.

Example 70(S)-2,4-dimethyl-1-(2-(trifluoromethyl)-4-(7-(trifluoromethyl)quinolin-4-yl)phenoxy)pentan-2-amine

Prepared as in Example 32. A mixture of2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (2.90 mg, 6.09μmol), potassium acetate (0.090 g, 0.913 mmol), 2^(nd) generation Xphosprecatalyst (2.395 mg, 3.04 μmol), 4-chloro-8-(trifluoromethyl)quinoline(0.0705 g, 0.304 mmol) and hypodiboric acid (0.041 g, 0.457 mmol) inethanol (4 mL) was degassed three times via vacuum/N₂ fill cycle. Thereaction mixture was heated at 80° C. for 3 h. The reaction was cooledto room temperature.(S)-1-(4-bromo-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(0.026 g, 0.073 mmol) and 2^(nd) generation Xphos precatalyst (2.395 mg,3.04 μmol) in THE (4 mL) was added to the reaction mixture, followed byaddition of potassium phosphate tribasic (3 mL, 1.500 mmol) at roomtemperature. The reaction mixture was underwent vacuum/N₂ fill cyclethree times before heated at 80° C. overnight. The reaction was cooledto rt then diluted with ethyl acetate and washed with water (3×). Theethyl acetate layer was separated, dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The crude was purified by reversephase HPLC (acetonitrile/water/10 mM ammonium acetate to afford(S)-2,4-dimethyl-1-(2-(trifluoromethyl)-4-(7-(trifluoromethyl)quinolin-4-yl)phenoxy)pentan-2-amine(8.9 mg, 0.018 mmol, 5% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 9.11 (d, J=4.3 Hz, 1H), 8.46 (s, 1H), 8.08 (d, J=8.5 Hz, 1H),7.90 (d, J=8.9 Hz, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.83 (s, 1H), 7.70 (d,J=4.3 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 3.94-3.87 (m, 2H), 1.82 (d, J=6.1Hz, 1H), 1.42 (d, J=5.5 Hz, 2H), 1.15 (s, 3H), 0.94 (dd, J=6.4, 2.1 Hz,6H); LCMS (ESI) m/e 471.3 [(M+H)⁺, calcd C₂₄H₂₅F₆N₂O, 471.2]; LC/MSretention time (method A): t_(R)=2.28 min.

Example 71(S)-1-(4-(7-fluoroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as in Example 32. Obtained(S)-1-(4-(7-fluoroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(4.2 mg, 9.89 umol, 2% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.96 (d, J=4.0 Hz, 1H), 7.97-7.79 (m, 3H), 7.77 (s, 1H),7.60-7.53 (m, 1H), 7.50 (d, J=4.0 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 3.89(d, J=7.6 Hz, 2H), 1.81 (d, J=6.4 Hz, 1H), 1.41 (d, J=5.2 Hz, 2H), 1.14(s, 3H), 0.93 (d, J=4.9 Hz, 6H); LCMS (ESI) m/e 404.2 [(M-NH₂)+, calcdC₂₃H₂₂F₄NO, 404.2]; LC/MS retention time (method B): t_(R)=1.88 min.

Example 72(S)-1-(4-(5,7-difluoroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as in Example 32. Obtained(S)-1-(4-(5,7-difluoroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(17.5 mg, 0.039 mmol, 23% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 9.02-8.96 (m, 1H), 7.82-7.76 (m, 1H), 7.73 (br. s., 2H), 7.56(br. s., 1H), 7.46 (d, J=4.3 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 3.88 (d,J=6.4 Hz, 2H), 1.82 (br. s., 1H), 1.42 (d, J=5.2 Hz, 2H), 1.15 (s, 3H),0.93 (d, J=6.6 Hz, 6H); LCMS (ESI) m/e 439.4 [(M+H)⁺, calcd C₂₃H₂₄F₅N₂O,439.2]; LC/MS retention time (method A): t_(R)=2.14 min.

Example 73(S)-1-(4-(6-fluoroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as in Example 32. Obtained(S)-1-(4-(6-fluoroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(9.6 mg, 0.023 mmol, 22% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.95 (d, J=4.4 Hz, 1H), 8.21 (dd, J=9.2, 5.5 Hz, 1H), 7.85(d, J=8.5 Hz, 1H), 7.79 (d, J=2.6 Hz, 1H), 7.75 (td, J=8.9, 2.9 Hz, 1H),7.57 (d, J=4.4 Hz, 1H), 7.50 (dd, J=10.3, 3.0 Hz, 1H), 7.44 (d, J=8.6Hz, 1H), 3.92 (q, J=8.9 Hz, 2H), 1.83 (dt, J=13.1, 6.7 Hz, 1H), 1.43 (d,J=5.5 Hz, 2H), 1.16 (s, 3H), 0.94 (dd, J=6.7, 3.2 Hz, 6H); ¹⁹F NMR (376MHz, DMSO-d6) δ −61.01, −244.69; LCMS (ESI) m/e 421.2 [(M+H)⁺, calcdC₂₃H₂₅F₄N₂O₁, 421.2]; LC/MS retention time (method B): t_(R)=1.80 min.

Example 74(S)-1-(2-cyclopropyl-4-(quinolin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as in Example 32.

Part A: (S)-tert-butyl(1-(2-cyclopropyl-4-(quinolin-4-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate

LCMS (ESI) m/e 475.1 [(M+H)⁺, calcd C₃H₃₉N₂O₃, 475.3]; LC/MS retentiontime (method B): t_(R)=2.21 min.

Part B:(S)-1-(2-cyclopropyl-4-(quinolin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine

Obtained (12.7 mg, 0.032 mmol, 33% yield) as an off-white solid. ¹H NMR(500 MHz, DMSO-d₆) δ 8.90 (d, J=4.4 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H),7.90 (d, J=8.5 Hz, 1H), 7.78 (t, J=7.6 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H),7.42 (d, J=4.4 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H),7.03 (s, 1H), 3.82 (s, 2H), 2.27 (p, J=6.9 Hz, 1H), 1.85 (dt, J=12.7,6.6 Hz, 1H), 1.47 (q, J=8.2, 7.0 Hz, 2H), 1.20 (s, 3H), 0.95 (q, J=7.9,7.2 Hz, 8H), 0.71 (t, J=4.1 Hz, 2H); LCMS (ESI) m/e 375.1 [(M+H)⁺, calcdC₂₅H₃₁N₂O₁, 375.2]; LC/MS retention time (method B): t_(R)=1.69 min.

Example 751-(2-chloro-6-fluoro-4-(quinolin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as in Example 29.

Part A: Benzyl(1-(4-bromo-2-chloro-6-fluorophenoxy)-2,4-dimethylpentan-2-yl)carbamate

An NMP (0.3 mL) suspension of 4-bromo-2-chloro-6-fluorophenol (23.00 mg,0.102 mmol), sodium carbonate (35 mg, 0.330 mmol) and benzyl4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(0.0334 g, 0.102 mmol) was heated at 50° C. overnight. The reaction wasdiluted with ethyl acetate and washed with water (3×). The ethyl acetatelayer was separated, dried (Na₂SO₄), filtered and concentrated underreduced pressure. The crude material was carried on without furtherpurification. LCMS (ESI) m/e 496.0 [(M+Na)⁺, calcd C₂H₂₄ClBrFNO₃Na,494.1]; LC/MS retention time (method B): t_(R)=2.59 min.

Part B: Benzyl(1-(2-chloro-6-fluoro-4-(quinolin-4-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate

LCMS (ESI) m/e 521.4 [(M+H)⁺, calcd C₃₀H₃₁ClFN₂O₃, 521.2]; LC/MSretention time (method A): t_(R)=2.38 min.

Part C:1-(2-chloro-6-fluoro-4-(quinolin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine

Triethylsilane(0.1 ml, 0.626 mmol) was added to a CH₂Cl₂ (0.2 mL)suspension of palladium(II) acetate (2 mg, 8.91 μmol) and triethylamine(0.1 ml, 0.717 mmol) at rt. The reaction turned black. The solution wasstirred at room temperature for 10 min before addition of CH₂Cl₂ (0.2mL) solution of benzyl(1-(2-chloro-6-fluoro-4-(quinolin-4-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate(0.0441 g, 0.085 mmol) (the flask contain the benzyl(1-(2-chloro-6-fluoro-4-(quinolin-4-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate(0.0441 g, 0.085 mmol) was rinsed with CH₂Cl₂ (0.2 mL) and added to thereaction mixture). The reaction was stirred at room temperatureovernight. The solvent was removed under reduced pressure and the crudematerial was purified via reverse phase HPLC (acetonitrile/water/10 mMammonium acetate) to afford1-(2-chloro-6-fluoro-4-(quinolin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine(8.9 mg, 0.022 mmol, 26% yield.) ¹H NMR (500 MHz, DMSO-d6) δ 8.96 (d,J=4.4 Hz, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.88 (s, 1H), 7.83 (s, 1H), 7.66(s, 1H), 7.60-7.50 (m, 3H), 3.98-3.90 (m, 2H), 1.89-1.81 (m, 1H), 1.44(dd, J=14.9, 5.7 Hz, 2H), 1.18 (s, 3H), 0.97 (dd, J=9.4, 6.8 Hz, 6H);LCMS (ESI) m/e 387.2 [(M+H)⁺, calcd C₂₂H₂₅FClN₂O, 387.2]; LC/MSretention time (method B): t_(R)=1.70 min.

Example 76(S)-1-((5-(7-fluoroquinolin-4-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Intermediates prepared as described in Example 19. A mixture ofpotassium acetate (0.026 g, 0.266 mmol),(S)-1-((5-bromo-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(0.0267 g, 0.089 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.027 g,0.106 mmol) in dioxane (1 mL) underwent vacuum/backfill N₂ (5×).PdCl₂(dppf) (1.946 mg, 2.66 μmol) was added to the reaction mixture andthe reaction was heated at 80° C. overnight. The reaction mixture wascooled to room temperature. PdCl₂(dppf) (3.26 mg, 4.45 μmol), sodiumcarbonate (0.089 mL, 0.178 mmol, 2N), 4-chloro-7-fluoroquinoline (16.16mg, 0.089 mmol) and(S)-2,4-dimethyl-1-((3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)pentan-2-amine(31.0 mg, 0.089 mmol) in dioxane (1.2 mL) were added to the vesselmixture and the mixture was degassed via vacuum/N₂ fill cycle threetimes. The reaction mixture was heated at 130° C. for 4 h. The reactionwas cooled to rt then diluted with ethyl acetate and washed with water(2×) followed by brine. The ethyl acetate layer was separated, dried(Na₂SO₄), filtered and concentrated under reduced pressure. The crudewas purified via reverse phase HPLC (acetonitrile/water/10 mM ammoniumacetate) to afford(S)-1-((5-(7-fluoroquinolin-4-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(15.2 mg, 0.041 mmol, 47% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.99-8.95 (m, 1H), 8.20-8.16 (m, 1H), 7.98 (dd, J=9.2, 6.2Hz, 1H), 7.88-7.83 (m, 1H), 7.81 (s, 1H), 7.59-7.53 (m, 1H), 7.49 (d,J=4.4 Hz, 1H), 4.11 (d, J=4.4 Hz, 2H), 3.46 (br. s., 2H), 1.90 (s, 3H),1.87-1.79 (m, 1H), 1.45 (t, J=6.2 Hz, 2H), 1.17 (s, 3H), 0.95 (t, J=6.1Hz, 6H); LCMS (ESI) m/e 386.2 [(M+H)⁺, calcd C₂₂H₂₇FN₃O, 386.2]; LC/MSretention time (method B): t_(R)=1.78 min.

Example 77(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(5,7-difluoroquinolin-4-yl)nicotinonitrile

Prepared as in Example 53.

Part A: (S)-tert-butyl(1-((5-bromo-3-cyanopyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

LCMS (ESI) m/e 434.1 [(M+Na)⁺, calcd C₁₈H₂₆BrN₃O₃Na, 434.1]; LC/MSretention time (method B): t_(R)=2.38 min.

Part B: 4-bromo-5,7-difluoroquinoline

To a 20 mL microwave tube was added 4-chloro-5,7-difluoroquinoline(0.159 g, 0.795 mmol) and propionitrile (1 mL), followed by TMS-Br(0.206 mL, 1.59 mmol) at room temperature. A precipitate formed. Thetube was sealed and heated to 100° C. overnight. The reaction was cooledto room temperature. The crude mixture was poured into iced NaOH (1N, 3mL) and the tube was washed with water.

The aqueous layer was extracted with diethyl ether (3×). The diethylether layers were combined, dried (Na₂SO₄), filtered and concentratedunder reduced pressure to give 4-bromo-5,7-difluoroquinoline (14.2 mg,0.582 mmol, 73% yield) as a yellow solid. LCMS (ESI) m/e 243.8 [(M+Na)⁺,calcd C₉H₅BrNF₂, 244.0]; LC/MS retention time (method B): t_(R)=2.04min.

Part C:5,7-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

A mixture of potassium acetate (0.122 g, 1.242 mmol),4-bromo-5,7-difluoroquinoline (0.1010 g, 0.414 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.126 g,0.497 mmol) in dioxane (3 mL) underwent a cycle of vacuum/backfill withnitrogen 5 times. PdCl₂(dppf) (9.09 mg, 0.012 mmol) was added to thereaction mixture at room temperature and the reaction was heated at 80°C. overnight. The crude was used as it is in the next step.

Part D: (S)-tert-butyl(1-((3-cyano-5-(5,7-difluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

A mixture of sodium carbonate (0.138 mL, 0.276 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (7.89 mg, 9.66 μmol),5,7-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline(0.040 g, 0.138 mmol) and (S)-tert-butyl(1-((5-bromo-3-cyanopyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(0.057 g, 0.138 mmol) in dioxane (2 mL) (degassed) was heated at 100° C.for 3 h. The reaction was diluted with ethyl acetate and washed withwater (3×). The ethyl acetate layer was dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (0-10-25% ethyl acetate in hexanes) to afford(S)-tert-butyl(1-((3-cyano-5-(5,7-difluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(0.0372 g, 0.075 mmol, 54% yield) as a brown solid. LCMS (ESI) m/e 519.0[(M+Na)⁺, calcd C₂₇H₃₀F₂N₄O₃Na, 519.2]; LC/MS retention time (method B):t_(R)=2.38 min.

Part E:(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(5,7-difluoroquinolin-4-yl)nicotinonitrile

¹H NMR (500 MHz, DMSO-d₆) δ 9.04 (d, J=4.4 Hz, 1H), 8.59 (s, 1H), 8.54(br. s., 1H), 7.82 (d, J=9.2 Hz, 1H), 7.70-7.59 (m, 1H), 7.54 (d, J=4.4Hz, 1H), 4.30-4.17 (m, 2H), 3.44 (br. s., 2H), 1.87-1.79 (m, 1H),1.50-1.36 (m, 2H), 1.16 (s, 3H), 0.96 (d, J=2.9 Hz, 3H), 0.94 (d, J=2.9Hz, 3H); LCMS (ESI) m/e 397.2 [(M+H)⁺, calcd C₂₂H₂₃F₂N₄O, 397.2]; LC/MSretention time (method B): t_(R)=2.39 min.

Example 78(S)-1-((3-chloro-5-(quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as in example 77.

Part A: Boc(S)-1-((3-chloro-5-(quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

(ESI) m/e 470.4 [(M+H)⁺, calcd C₂₆H₃₃ClN₃O₃, 470.2]; LC/MS retentiontime (method A): t_(R)=2.45 min.

Part B:(S)-1-((3-chloro-5-(quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

¹H NMR (500 MHz, DMSO-d₆) δ 8.99 (d, J=4.4 Hz, 1H), 8.36 (d, J=1.8 Hz,1H), 8.25 (d, J=1.8 Hz, 1H), 7.96 (s, 1H), 7.89-7.80 (m, 2H), 7.67 (t,J=7.5 Hz, 1H), 7.55 (d, J=4.4 Hz, 1H), 4.59-4.42 (m, 2H), 1.94-1.61 (m,3H), 1.43 (s, 3H), 0.98 (t, J=6.4 Hz, 6H); LCMS (ESI) m/e 370.3 [(M+H)⁺,calcd C₂₁H₂₅ClN₃O, 370.2]; LC/MS retention time (method A): t_(R)=2.09min.

Example 79(S)-1-((3-methoxy-5-(quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as in Example 77. Obtained(S)-1-((3-methoxy-5-(quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(5.4 mg, 0.014 mmol, 23% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.96 (d, J=4.4 Hz, 1H), 8.12 (d, J=8.4 Hz, 1H), 7.97 (d,J=8.4 Hz, 1H), 7.86 (d, J=1.5 Hz, 1H), 7.82 (t, J=7.5 Hz, 1H), 7.64 (t,J=7.7 Hz, 1H), 7.53 (d, J=4.4 Hz, 1H), 7.51 (d, J=1.5 Hz, 1H), 4.17-4.06(m, 2H), 3.60 (br. s., 3H), 1.84 (dt, J=12.8, 6.4 Hz, 1H), 1.47-1.36 (m,2H), 1.15 (s, 3H), 0.95 (t, J=7.2 Hz, 6H); LCMS (ESI) m/e 366.0 [(M+H)⁺,calcd C₂₂H₂₈N₃O₂, 366.2]; LC/MS retention time (method B): t_(R)=1.55min.

Example 80(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(1,6-naphthyridin-4-yl)nicotinonitrile

Prepared as in Example 77.

Part A: (S)-tert-butyl(1-((3-cyano-5-(1,6-naphthyridin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

LCMS (ESI) m/e 484.2 [(M+Na)⁺, calcd C₂₆H₃₁F₂N₅Na₁O₃, 484.2]; LC/MSretention time (method B): t_(R)=2.14 min.

Part B:(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(1,6-naphthyridin-4-yl)nicotinonitrile

Obtained(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(1,6-naphthyridin-4-yl)nicotinonitrile(22 mg, 0.058 mmol, 66% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 9.28 (s, 1H), 9.23 (d, J=4.4 Hz, 1H), 8.84 (d, J=5.7 Hz, 1H),8.78 (d, J=2.4 Hz, 1H), 8.75 (d, J=2.5 Hz, 1H), 8.04 (d, J=5.8 Hz, 1H),7.74 (d, J=4.5 Hz, 1H), 4.68 (d, J=11.6 Hz, 1H), 4.56 (d, J=11.5 Hz,1H), 1.89 (dq, J=12.7, 6.2 Hz, 1H), 1.81 (dd, J=14.4, 5.5 Hz, 1H), 1.64(dd, J=14.4, 5.6 Hz, 1H), 1.44 (s, 3H), 1.01 (d, J=6.6 Hz, 6H); LCMS(ESI) m/e 362.2 [(M+H)⁺, calcd C₂₁H₂₄N₅O₁, 362.2]; LC/MS retention time(method B): t_(R)=1.56 min.

Example 81(S)-2,4-dimethyl-1-((2-methyl-6-(quinolin-4-yl)pyridin-3-yl)oxy)pentan-2-amine

Prepared as in Example 77. Obtained(S)-2,4-dimethyl-1-((2-methyl-6-(quinolin-4-yl)pyridin-3-yl)oxy)pentan-2-amine(10.3 mg, 0.028 mmol, 43% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.96 (d, J=4.4 Hz, 1H), 8.25 (d, J=8.5 Hz, 1H), 8.10 (d,J=8.5 Hz, 1H), 7.79 (t, J=7.6 Hz, 1H), 7.65-7.56 (m, 3H), 7.51 (d, J=8.4Hz, 1H), 3.81 (d, J=2.2 Hz, 2H), 2.53 (s, 3H), 1.84 (dq, J=12.6, 6.4 Hz,1H), 1.50-1.38 (m, 2H), 1.17 (s, 3H), 0.96 (t, J=6.2 Hz, 6H); LCMS (ESI)m/e 350.3 [(M+H)⁺, calcd C₂₂H₂₈N₃O₁, 350.2]; LC/MS retention time(method A): t_(R)=1.86 min.

Example 82(S)-2,4-dimethyl-1-((4-methyl-6-(quinolin-4-yl)pyridin-3-yl)oxy)pentan-2-amine

Prepared as in Example 77. Obtained(S)-2,4-dimethyl-1-((4-methyl-6-(quinolin-4-yl)pyridin-3-yl)oxy)pentan-2-amine(11 mg, 0.030 mmol, 39% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.97 (d, J=4.4 Hz, 1H), 8.44 (s, 1H), 8.25 (d, J=8.8 Hz, 1H),8.10 (d, J=8.4 Hz, 1H), 7.80 (t, J=7.7 Hz, 1H), 7.67-7.57 (m, 3H), 3.94(s, 2H), 2.34 (s, 3H), 1.87-1.81 (m, 1H), 1.52-1.40 (m, 2H), 1.18 (s,3H), 0.96 (t, J=6.8 Hz, 6H); LCMS (ESI) m/e 350.1 [(M+H)⁺, calcdC₂₂H₂₈N₃O, 350.2]; LC/MS retention time (method B): t_(R)=1.67 min.

Example 83(S)-1-((2-chloro-6-(quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as in Example 77.

Part A: (S)-tert-butyl(1-((2-chloro-6-(quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

LCMS (ESI) m/e 470.0 [(M+H)⁺, calcd C₂₆H₃₃ClN₃O₃, 470.2]; LC/MSretention time (method B): t_(R)=2.15 min.

Part B:(S)-1-((2-chloro-6-(quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Obtained (6.3 mg, 0.016 mmol, 36% yield) as an off-white solid. ¹H NMR(500 MHz, DMSO-d₆) δ 9.00 (d, J=4.4 Hz, 1H), 8.20 (d, J=8.5 Hz, 1H),8.13 (d, J=8.4 Hz, 1H), 7.86-7.77 (m, 3H), 7.69-7.60 (m, 2H), 3.97-3.87(m, 2H), 1.85 (dt, J=12.8, 6.5 Hz, 1H), 1.44 (t, J=4.8 Hz, 2H), 1.17 (s,3H), 0.96 (t, J=6.0 Hz, 6H); LCMS (ESI) m/e 370.0 [(M+H)⁺, calcdC₂₁H₂₅Cl₁N₃O₁, 370.2]; LC/MS retention time (method B): t_(R)=1.57 min.

Example 84(S)-1-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as in example 19 to obtain(S)-1-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(27 mg, 0.069 mmol, 79% yield) as an off-white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.36 (d, J=5.0 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.89(dd, J=8.5, 2.0 Hz, 1H), 7.41 (d, J=3.5 Hz, 1H), 7.18-7.08 (m, 2H), 6.68(d, J=3.5 Hz, 1H), 3.92-3.84 (m, 2H), 1.82-1.77 (m, 1H), 1.60-1.48 (m,2H), 1.28 (s, 3H), 1.01 (dd, J=9.0, 6.8 Hz, 6H); ¹⁹F NMR (376 MHz,CHLOROFORM-d) δ −62.31 (s, 3F); LCMS (ESI) m/e 392.2 [(M+H)⁺, calcdC₂₁H₂₅F₃N₃O, 392.2]; LC/MS retention time (method B): t_(R)=1.81 min.

Example 85(S)-1-(4-(1,6-naphthyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

Part A: 4-(4-methoxy-3-(trifluoromethyl)phenyl)-1,6-naphthyridine

To a 20 mL vial was added 4-chloro-1,6-naphthyridine (200 mg, 1.215mmol), (4-methoxy-3-(trifluoromethyl)phenyl)boronic acid (321 mg, 1.458mmol), and potassium phosphate tribasic (4.86 mL, 2.430 mmol) in THE(2.5 mL) to give a yellow suspension. After degassing with N₂ for 5 min,2^(nd) generation XPHOS precatalyst (19.12 mg, 0.024 mmol) was added.The mixture was sealed under nitrogen and heated at 40° C. for 2 h. Thereaction mixture was cooled to rt and diluted with water and EtOAc. Thelayers were separated. The organic layer was washed with brine, dried(Na₂SO₄) and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (up to 8% MeOH/CH₂Cl₂) to afford4-(4-methoxy-3-(trifluoromethyl)phenyl)-1,6-naphthyridine (369 mg, 1.213mmol, quantitative yield) as a light yellow solid: ¹H NMR (400 MHz,Chloroform-d) δ 9.37 (d, J=0.9 Hz, 1H), 9.14 (d, J=4.5 Hz, 1H), 8.83 (d,J=5.9 Hz, 1H), 8.03 (dd, J=6.0, 0.9 Hz, 1H), 7.80 (d, J=2.2 Hz, 1H),7.73 (dd, J=8.5, 2.2 Hz, 1H), 7.47 (d, J=4.5 Hz, 1H), 7.23 (d, J=8.6 Hz,1H), 4.05 (s, 3H); ¹⁹F NMR (376 MHz, Chloroform-d) δ −62.63; LCMS (ESI)m/e 305.2 [(M+H)⁺, calcd C₁₆H₁₂F₃N₂O₁, 305.1]; LC/MS retention time(method A): t_(R)=1.86 min.

Part B: 4-(1,6-naphthyridin-4-yl)-2-(trifluoromethyl)phenol

To a 250 mL round-bottomed flask was added4-(4-methoxy-3-(trifluoromethyl)phenyl)-1,6-naphthyridine (369 mg, 1.213mmol) in CH₂Cl₂ (5 mL) under nitrogen to give a yellow solution. BBr₃(12.13 mL, 12.13 mmol) was slowly added. The mixture was refluxed undernitrogen for 5 h. The reaction was slowly quenched with 1N NaOH toadjust the pH to ˜5. EtOAc was added. The layers were separated. Theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with brine, dried (Na₂SO₄) and concentrated under reducedpressure. The residue was purified by silica gel chromatography (up to8% MeOH/CH₂Cl₂) to afford4-(1,6-naphthyridin-4-yl)-2-(trifluoromethyl)phenol (124 mg, 0.427 mmol,35%) as a white solid: ¹H NMR (400 MHz, Chloroform-d) δ 9.45 (s, 1H),9.21 (d, J=4.7 Hz, 1H), 8.84 (d, J=6.1 Hz, 1H), 8.16 (d, J=6.1 Hz, 1H),7.89-7.75 (m, 1H), 7.60 (q, J=3.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 1H); ¹⁹FNMR (376 MHz, Chloroform-d) δ −62.58; LCMS (ESI) m/e 291.2 [(M+H)⁺,calcd C₁₅H₁₀F₃N₂O₁, 291.2]; LC/MS retention time (method B): t_(R)=1.59min.

Part C: (S)-tert-butyl(1-(4-(1,6-naphthyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate

LCMS (ESI) m/e 526.2 [(M+Na)⁺, calcd C₂₇H₃₂F₃N₃Na₁O₃, 526.2]; LC/MSretention time (method B): t_(R)=2.31 min.

Part D:(S)-1-(4-(1,6-naphthyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

Obtained (35.7 mg, 0.087 mmol, 99% yield) as an off-white solid. ¹H NMR(500 MHz, DMSO-d6) δ 9.26 (s, 1H), 9.17 (d, J=4.5 Hz, 1H), 8.80 (d,J=5.8 Hz, 1H), 8.01 (d, J=5.9 Hz, 1H), 7.95 (d, J=8.7 Hz, 1H), 7.90 (s,1H), 7.69 (d, J=4.4 Hz, 1H), 7.47 (d, J=8.6 Hz, 1H), 3.94 (q, J=9.0 Hz,2H), 1.83 (dq, J=12.9, 6.4 Hz, 1H), 1.44 (dd, J=5.8, 2.6 Hz, 2H), 1.17(s, 3H), 0.94 (dd, J=6.8, 3.3 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ−61.02; LCMS (ESI) m/e 404.2 [(M+H)⁺, calcd C₂₂H₂₅F₃N₃O₁, 362.2]; LC/MSretention time (method B): t_(R)=1.79 min.

Example 86(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(1,6-naphthyridin-4-yl)benzonitrile

Prepared as in Example 51.

Part A: (S)-tert-butyl(1-(4-bromo-2-cyanophenoxy)-2,4-dimethylpentan-2-yl)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J=2.5 Hz, 1H), 7.58 (dd,J=9.0, 2.5 Hz, 1H), 6.91 (d, J=9.0 Hz, 1H), 4.57 (s, 1H), 4.31 (d, J=9.0Hz, 1H), 4.09 (d, J=9.0 Hz, 1H), 1.90 (dd, J=14.0, 6.5 Hz, 1H),1.86-1.75 (m, 1H), 1.47 (dd, J=14.0, 5.0 Hz, 1H), 1.39 (s, 3H), 1.37 (s,9H), 0.99 (d, J=1.9 Hz, 3H), 0.97 (d, J=1.9 Hz, 3H); LCMS (ESI) m/e432.9 [(M+Na)⁺, calcd C₁₉H₂₇BrN₂NaO₃, 433.1]; LC/MS retention time(method B): t_(R)=2.38 min.

Part B: (S)-tert-butyl(1-(2-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate

LCMS (ESI) m/e 481.1 [(M+Na)⁺, calcd C₂₅H₃₉BN₂NaO₅, 481.3]; LC/MSretention time (method B): t_(R)=2.49 min.

Part C: (S)-tert-butyl(1-(2-cyano-4-(1,6-naphthyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate

LCMS (ESI) m/e 483.1 [(M+Na)⁺, calcd C₂₇H₃₂N₄Na₁O₃, 483.2]; LC/MSretention time (method B): t_(R)=2.10 min.

Part D:(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(1,6-naphthyridin-4-yl)benzonitrile

Obtained(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(1,6-naphthyridin-4-yl)benzonitrile(6.7 mg, 0.017 mmol, 34% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 9.27 (s, 1H), 9.17 (d, J=4.5 Hz, 1H), 8.80 (d, J=5.8 Hz, 1H),8.11 (d, J=2.2 Hz, 1H), 8.01 (d, J=5.8 Hz, 1H), 7.97 (dd, J=8.7, 2.3 Hz,1H), 7.67 (d, J=4.5 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 4.03-3.92 (m, 2H),1.85 (dt, J=12.6, 6.3 Hz, 1H), 1.51-1.40 (m, 2H), 1.18 (s, 3H), 0.96(dd, J=6.7, 4.3 Hz, 6H); LCMS (ESI) m/e 361.0 [(M+H)⁺, calcd C₂₂H₂₅N₄O₁,361.2]; LC/MS retention time (method B): t_(R)=1.58 min.

Example 87(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(1,5-naphthyridin-4-yl)benzonitrile

Prepared as in Example 51.

Part A: (S)-tert-butyl(1-(2-cyano-4-(1,5-naphthyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate

LCMS (ESI) m/e 483.1 [(M+Na)⁺, calcd C₂₇H₃₂N₄Na₁O₃, 483.2]; LC/MSretention time (method B): t_(R)=2.22 min.

Part B:(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(1,5-naphthyridin-4-yl)benzonitrile

Obtained (5.5 mg, 0.015 mmol, 29% yield) as an off-white solid. ¹H NMR(500 MHz, DMSO-d₆) δ 9.06 (t, J=4.6 Hz, 2H), 8.51 (d, J=8.4 Hz, 1H),8.23 (d, J=2.3 Hz, 1H), 8.18-8.11 (m, 1H), 7.90-7.82 (m, 2H), 7.41 (d,J=8.9 Hz, 1H), 3.65 (s, 2H), 1.84 (dt, J=12.4, 6.5 Hz, 1H), 1.45 (dd,J=5.6, 2.5 Hz, 2H), 1.17 (s, 3H), 0.95 (dd, J=6.7, 3.9 Hz, 6H). (OCH2was likely buried in a broad peak); LCMS (ESI) m/e 361.0 [(M+H)⁺, calcdC₂₂H₂₅N₄O₁, 361.2]; LC/MS retention time (method B): t_(R)=1.68 min.

Example 88(S)-1-(4-(7-chloroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

Part A: 7-chloro-4-(4-methoxy-3-(trifluoromethyl)phenyl)quinoline

A mixture of 4,7-dichloroquinoline (810 mg, 4.09 mmol),(4-methoxy-3-(trifluoromethyl)phenyl)boronic acid (900 mg, 4.09 mmol),PdCl₂(dppf) (150 mg, 0.205 mmol), cesium carbonate (2000 mg, 6.14 mmol),and 1,4-dioxane (10 mL) were charged to a 20 mL pressure rated vial anda stream of nitrogen was bubbled through for 10 minutes. The vial wassealed, purged of oxygen, and stirred at 90° C. overnight. The resultantmixture was vacuum filtered and the filtrate concentrated under reducedpressure. The reside was purified by silica gel chromatography (5-40%ethyl acetate/hexanes gradient elution) to afford7-chloro-4-(4-methoxy-3-(trifluoromethyl)phenyl)quinoline (1.04 g, 3.08mmol, 75% yield) as a white solid. The material was carried on withoutfurther purification. LCMS (ESI) m/e 338.1 [(M+H)⁺, calcd C₁₇H₂ClF₃NO,338.1]; LC/MS retention time (method D): t_(R)=1.13 min.

Part B: 4-(7-chloroquinolin-4-yl)-2-(trifluoromethyl)phenol

A solution of 7-chloro-4-(4-methoxy-3-(trifluoromethyl)phenyl)quinoline(0.51 g, 1.510 mmol) in dichloromethane (10 mL) 0° C. was treated withBBr₃ (3.02 mL, 3.02 mmol). The cooling bath was removed and the reactionsolution stirred at ambient temperature overnight. The resultant wascooled to 0° C. and quenched with saturated aqueous sodium bicarbonate.The layers were separated and the aqueous layer was extracted with ethylacetate (2×10 mL). The combined organics were dried over magnesiumsulfate, filtered, and concentrated under reduced pressure to give anorange solid. The crude residue was adsorbed onto silica gel andpurified by silica gel chromatography (10-80% ethyl acetate/hexanes) toafford 4-(7-chloroquinolin-4-yl)-2-(trifluoromethyl)phenol (195 mg,0.271 mmol, 18% yield) as a pale yellow solid. LCMS (ESI) m/e 323.9[(M+H)⁺, calcd C₁₆H₁₀ClF₃NO, 324.0]; LC/MS retention time (method D):t_(R)=1.00 min.

Part C: (S)-tert-butyl(1-(4-(7-chloroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate

A mixture of 4-(7-chloroquinolin-4-yl)-2-(trifluoromethyl)phenol (195mg, 0.602 mmol), (S)-tert-butyl4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (194mg, 0.663 mmol), cesium carbonate (393 mg, 1.205 mmol), andN,N-dimethylformamide (4 mL) was heated to 80° C. overnight. Theresultant mixture was cooled to room temperature and diluted with ethylacetate (40 mL). The organic layer was washed with brine (3×15 mL),dried over magnesium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by purified by silica gelchromatography to afford (S)-tert-butyl(1-(4-(7-chloroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate(160 mg, 0.298 mmol, 50% yield) as a pale purple oil. LCMS (ESI) m/e537.4 [(M+H)⁺, calcd C₂₈H₃₃ClF₃N₂O₃, 537.2]; LC/MS retention time(method A): t_(R)=2.60 min; ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.95 (d,J=4.3 Hz, 1H), 8.19 (d, J=2.3 Hz, 1H), 7.81 (d, J=9.0 Hz, 1H), 7.71 (d,J=2.0 Hz, 1H), 7.62 (dd, J=8.5, 2.0 Hz, 1H), 7.50 (dd, J=8.9, 2.1 Hz,1H), 7.33 (d, J=4.5 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 4.39-4.17 (m, 2H),2.00-1.79 (m, 3H), 1.44 (s, 3H), 1.42 (s, 9H), 1.03 (d, J=6.5 Hz, 3H),1.01 (d, J=6.5 Hz, 3H).

Part D:(S)-1-(4-(7-chloroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

(S)-tert-Butyl(1-(4-(7-chloroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate(40 mg, 0.074 mmol) was treated with TFA (1 mL, 12.98 mmol) and stirredat ambient temperature for 30 min. The resultant was concentrated underreduced pressure. The residue was purified via preparative LC/MS(Column: XBridge C18, 19×200 mm, 5-am; Mobile Phase A: 5:95acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile: water with 10-mM ammonium acetate; Gradient: 45-85% B over15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.). Obtained(S)-1-(4-(7-chloroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-aminecarbamate (160 mg, 0.298 mmol, 50% yield) as a colorless solid. LCMS(ESI) m/e 437.2 [(M+H)⁺, calcd C₂₃H₂₅ClF₃N₂O, 437.2]; LC/MS retentiontime (method D): t_(R)=0.97 min; ¹H NMR (500 MHz, DMSO-d₆) δ 8.98 (d,J=4.4 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H), 7.88 (d, J=9.2 Hz, 1H), 7.83 (d,J=8.8 Hz, 1H), 7.78 (s, 1H), 7.66 (dd, J=9.2, 1.8 Hz, 1H), 7.55 (d,J=4.4 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 3.96-3.83 (m, 2H), 1.86-1.77 (m,1H), 1.41 (d, J=5.5 Hz, 2H), 1.14 (s, 3H), 0.94 (d, J=6.6 Hz, 3H), 0.93(d, J=6.6 Hz, 3H).

Example 89(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)quinoline-7-carbonitrile

Part A: (S)-tert-butyl(1-(4-(7-cyanoquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate

(S)-tert-butyl(1-(4-(7-chloroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate(84 mg, 0.156 mmol) (prepared as described in Example 88), zinc cyanide(20.20 mg, 0.172 mmol), 1,1′-bis(diphenylphosphino)ferrocene (13.01 mg,0.023 mmol), Pd2(dba)3 (7.16 mg, 7.82 μmol), N,N-dimethylformamide (1mL), and water (0.10 mL) were charged to a pressure rated vial and themixture was sparged with nitrogen for 5 minutes. The vial was sealed,purged of oxygen, and heated under nitrogen at 115° C. overnight. Theresultant mixture was cooled to ambient temperature, vacuum filtered,and concentrated under reduced pressure. The residue was purified bysilica gel chromatography (10-80% ethyl acetate/hexanes gradientelution) to afford (S)-tert-butyl(1-(4-(7-cyanoquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate(22.5 mg, 0.043 mmol, 27% yield) as a near colorless film. LCMS (ESI)m/e 528.2 [(M+H)⁺, calcd C₂₉H₃₃F₃N₃O₃, 528.3]; LC/MS retention time(method D): t_(R)=1.30 min.

Part B:(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)quinoline-7-carbonitrile

(S)-tert-Butyl(1-(4-(7-cyanoquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate(22 mg, 0.042 mmol) was treated with TFA (964 μL, 12.51 mmol) andstirred at room temperature for 30 minutes. The resultant wasconcentrated under reduced pressure. The residue was purified viapreparative LC/MS (Column: XBridge C18, 19×200 mm, 5-am; Mobile Phase A:5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 45-85% Bover 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.).Obtained(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)quinoline-7-carbonitrile(13.3 mg, 0.031 mmol, 75% yield) as a colorless solid. LCMS (ESI) m/e428.2 [(M+H)⁺, calcd C₂₄H₂₅F₃N₃O, 428.2]; LC/MS retention time (methodD): t_(R)=0.97 min; ¹H NMR (500 MHz, DMSO-d₆) δ 9.11 (d, J=4.4 Hz, 1H),8.68 (s, 1H), 8.06-7.98 (m, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.84 (d, J=8.8Hz, 1H), 7.81 (s, 1H), 7.70 (d, J=4.4 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H),4.00-3.77 (m, 2H), 1.82 (dt, J=12.7, 6.3 Hz, 1H), 1.41 (d, J=5.5 Hz,2H), 1.14 (s, 3H), 0.94 (d, J=6.5 Hz, 3H), 0.93 (d, J=6.5 Hz, 3H).

Example 90(S)-2,4-dimethyl-1-(2-methyl-4-(2-methylpyridin-4-yl)phenoxy)pentan-2-amine

Prepared as described in Example 32 to afford(S)-2,4-dimethyl-1-(2-methyl-4-(2-methylpyridin-4-yl)phenoxy)pentan-2-aminecarbonitrile (17 mg, 0.054 mmol, 98% yield for the final step) as acolorless solid. LCMS (ESI) m/e 313.1 [(M+H)⁺, calcd C₂₀H₂₉N₂O, 313.2];LC/MS retention time (method D): t_(R)=0.65 min; ¹H NMR (500 MHz,DMSO-d₆) δ 8.44 (d, J=5.1 Hz, 1H), 7.67-7.60 (m, 2H), 7.54 (s, 1H), 7.45(d, J=5.1 Hz, 1H), 7.05 (d, J=8.1 Hz, 1H), 3.88-3.29 (m, 2H), 2.30 (s,3H), 1.91 (s, 3H), 1.81 (dt, J=12.8, 6.4 Hz, 1H), 1.64-1.55 (m, 1H),1.53-1.44 (m, 1H), 1.26 (s, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6Hz, 3H).

Example 91(S)-1-(2-fluoro-4-(2-methylpyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 32 to afford(S)-1-(2-fluoro-4-(2-methylpyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine(12 mg, 0.037 mmol, 96% yield for the final step) as a colorless solid.LCMS (ESI) m/e 317.1 [(M+H)⁺, calcd C₁₉H₂₆FN₂O, 317.2]; LC/MS retentiontime (method D): t_(R)=0.62 min; H NMR (500 MHz, DMSO-d₆) δ 8.57 (d,J=5.5 Hz, 1H), 8.13 (br. s., 2H), 7.87 (d, J=12.5 Hz, 1H), 7.80 (s, 1H),7.74 (d, J=9.2 Hz, 1H), 7.70 (d, J=5.1 Hz, 1H), 7.42 (t, J=8.6 Hz, 1H),4.23-4.08 (m, 2H), 2.58 (s, 3H), 1.82 (dt, J=12.7, 6.1 Hz, 1H),1.77-1.69 (m, 1H), 1.60 (dd, J=14.3, 5.1 Hz, 1H), 1.38 (s, 3H), 0.97 (d,J=6.6 Hz, 3H), 0.93 (d, J=6.2 Hz, 3H).

Example 92(S)-1-(4-(2-fluoropyridin-4-yl)-2-methylphenoxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 32 to afford(S)-1-(4-(2-fluoropyridin-4-yl)-2-methylphenoxy)-2,4-dimethylpentan-2-amine(4.8 mg, 0.015 mmol, 90% yield for the final step) as a colorless solid.LCMS (ESI) m/e 317.1 [(M+H)⁺, calcd C₁₉H₂₆FN₂O, 317.2]; LC/MS retentiontime (method D): t_(R)=0.96 min; ¹H NMR (500 MHz, DMSO-d₆) δ 8.24 (d,J=5.1 Hz, 1H), 7.80-7.69 (m, 2H), 7.66 (d, J=5.1 Hz, 1H), 7.47 (s, 1H),7.03 (d, J=8.1 Hz, 1H), 3.80-3.38 (m, 2H), 2.28 (s, 3H), 1.86-1.77 (m,1H), 1.49-1.35 (m, 2H), 1.15 (s, 3H), 0.93 (t, J=6.2 Hz, 6H).

Example 93(S)-1-(2-fluoro-4-(2-fluoropyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 32 to afford(S)-1-(2-fluoro-4-(2-fluoropyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine(10.8 mg, 0.034 mmol, 75% yield for the final step) as a colorlesssolid. LCMS (ESI) m/e 321.1 [(M+H)⁺, calcd C₁₈H₂₃F₂N₂O, 321.2]; LC/MSretention time (method D): t_(R)=0.90 min; ¹H NMR (500 MHz, DMSO-d₆) δ8.27 (d, J=5.1 Hz, 1H), 7.86 (dd, J=12.7, 2.0 Hz, 1H), 7.72 (d, J=5.9Hz, 2H), 7.55 (s, 1H), 7.30 (t, J=8.8 Hz, 1H), 3.88-3.75 (m, 2H), 1.81(dquin, J=12.7, 6.3 Hz, 1H), 1.48-1.31 (m, 2H), 1.13 (s, 3H), 0.93 (t,J=7.2 Hz, 6H).

Example 94(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-fluoropyridin-4-yl)benzonitrile

Prepared as described in Example 32 to afford(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-fluoropyridin-4-yl)benzonitrile(16.9 mg, 0.051 mmol, 80% yield for the final step) as a colorlesssolid. LCMS (ESI) m/e 328.1 [(M+H)⁺, calcd C₁₉H₂₃FN₃O, 328.2]; LC/MSretention time (method D): t_(R)=0.94 min; ¹H NMR (500 MHz, DMSO-d₆) δ8.37 (d, J=2.2 Hz, 1H), 8.31 (d, J=5.1 Hz, 1H), 8.22 (dd, J=8.8, 2.2 Hz,1H), 7.78 (d, J=5.1 Hz, 1H), 7.63 (s, 1H), 7.43 (d, J=9.2 Hz, 1H),4.12-3.99 (m, 2H), 1.83 (dt, J=12.7, 6.3 Hz, 1H), 1.60-1.43 (m, 2H),1.24 (s, 3H), 0.95 (t, J=6.4 Hz, 6H).

Example 95(S)-1-((2′-fluoro-5-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 32 to afford(S)-1-((2′-fluoro-5-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine(6.5 mg, 0.020 mmol, 57% yield for the final step) as a colorless solid.LCMS (ESI) m/e 318.1 [(M+H)⁺, calcd C₁₈H₂₅FN₃O, 318.2]; LC/MS retentiontime (method D): t_(R)=0.95 min; ¹H NMR (500 MHz, DMSO-d₆) δ 8.54 (d,J=2.2 Hz, 1H), 8.29 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.73 (d, J=5.1 Hz,1H), 7.57 (s, 1H), 4.22-4.08 (m, 2H), 1.91 (s, 3H), 1.81 (dq, J=12.7,6.2 Hz, 1H), 1.55-1.39 (m, 2H), 1.20 (s, 3H), 0.93 (dd, J=8.8, 6.6 Hz,6H).

Example 96(S)-4-(6-((2-amino-2,4-dimethylpentyl)oxy)-5-methylpyridin-3-yl)quinoline-7-carbonitrile

Prepared as described in Example 89 to afford(S)-4-(6-((2-amino-2,4-dimethylpentyl)oxy)-5-methylpyridin-3-yl)quinoline-7-carbonitrile(9.9 mg, 0.026 mmol, 35% yield for the final step) as a colorless solid.LCMS (ESI) m/e 375.1 [(M+H)⁺, calcd C₂₃H₂₇N₄O, 375.2]; LC/MS retentiontime (method D): t_(R)=0.94 min; ¹H NMR (600 MHz, DMSO-d₆) δ 9.10 (d,J=4.4 Hz, 1H), 8.68 (s, 1H), 8.18 (s, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.92(d, J=8.4 Hz, 1H), 7.82 (br. s., 1H), 7.68 (d, J=4.0 Hz, 1H), 4.17-4.05(m, 2H), 2.29 (s, 3H), 1.90-1.79 (m, 1H), 1.49-1.37 (m, 2H), 1.16 (s,3H), 0.95 (t, J=6.2 Hz, 6H).

Example 97(S)-1-((5-fluoro-2′-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 32 to afford(S)-1-((5-fluoro-2′-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine(4.8 mg, 0.015 mmol, 90% yield for the final step) as a colorless solid.LCMS (ESI) m/e 318.2 [(M+H)⁺, calcd C₁₈H₂₅FN₃O, 318.2]; LC/MS retentiontime (method D): t_(R)=0.60 min; ¹H NMR (500 MHz, DMSO-d₆) δ 8.51 (d,J=5.1 Hz, 1H), 8.48 (s, 1H), 8.23 (d, J=11.4 Hz, 1H), 7.66 (s, 1H), 7.57(d, J=5.1 Hz, 1H), 4.32-4.21 (m, 2H), 1.91 (s, 3H), 1.87-1.77 (m, 1H),1.57-1.41 (m, 2H), 1.22 (s, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6Hz, 3H).

Example 98(S)-1-((3-fluoro-5-(quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 32 to afford(S)-1-((3-fluoro-5-(quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(8.4 mg, 0.024 mmol, 59% yield for the final step) as a colorless solid.LCMS (ESI) m/e 354.1 [(M+H)⁺, calcd C₂₁H₂₅FN₃O, 354.2]; LC/MS retentiontime (method D): t_(R)=0.74 min; ¹H NMR (500 MHz, DMSO-d₆) δ 8.98 (d,J=4.0 Hz, 1H), 8.18 (d, J=1.8 Hz, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.03 (d,J=11.0 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.84 (t, J=7.5 Hz, 1H),7.70-7.62 (m, 1H), 7.54 (d, J=4.4 Hz, 1H), 4.27-4.17 (m, 2H), 1.85 (dt,J=12.7, 6.1 Hz, 1H), 1.53-1.38 (m, 2H), 1.19 (s, 3H), 0.96 (t, J=7.0 Hz,6H).

Example 99(S)-4-(6-((2-amino-2,4-dimethylpentyl)oxy)-5-fluoropyridin-3-yl)quinoline-7-carbonitrile

Prepared as described in Example 88 to(S)-4-(6-((2-amino-2,4-dimethylpentyl)oxy)-5-fluoropyridin-3-yl)quinoline-7-carbonitrile(5.6 mg, 0.014 mmol, 62% yield for the final step) as a colorless solid.LCMS (ESI) m/e 379.1 [(M+H)⁺, calcd C₂₂H₂₄FN₄O, 379.2]; LC/MS retentiontime (method D): t_(R)=0.91 min; ¹H NMR (500 MHz, DMSO-d₆) δ 9.13 (d,J=4.4 Hz, 1H), 8.70 (s, 1H), 8.19 (d, J=1.8 Hz, 1H), 8.09 (d, J=8.8 Hz,1H), 8.06-8.01 (m, 1H), 7.98-7.90 (m, 1H), 7.73 (d, J=4.4 Hz, 1H),4.22-4.10 (m, 2H), 1.85 (dt, J=12.7, 6.3 Hz, 1H), 1.50-1.35 (m, 2H),1.15 (s, 3H), 0.95 (t, J=6.6 Hz, 6H).

Example 100(S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)-3-fluoropyridin-2-yl)carbamate

Part A: (S)-tert-butyl(1-(4-bromo-2-cyanophenoxy)-2,4-dimethylpentan-2-yl)carbamate

Prepared as in Example 32 Parts A-F to yield (S)-tert-butyl(1-(4-bromo-2-cyanophenoxy)-2,4-dimethylpentan-2-yl)carbamate. LC/MSretention time (method D): t_(R)=1.29 min.

Part B: (S)-tert-butyl(1-(2-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate

(S)-tert-butyl(1-(4-bromo-2-cyanophenoxy)-2,4-dimethylpentan-2-yl)carbamate (0.57 g,1.386 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(0.422 g, 1.663 mmol), PdCl₂(dppf) (0.051 g, 0.069 mmol), potassiumacetate (0.408 g, 4.16 mmol), and dioxane (5 mL) were charged to apressure rated vial. The vial was purged of oxygen and the mixturestirred under nitrogen at 80° C. overnight. The mixture was cooled toambient temperature, vacuum filtered, and concentrated under reducedpressure. Obtained (S)-tert-butyl(1-(2-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate(600 mg, 1.30 mmol, 100% crude yield) as a brown oil that was usedwithout further purification. LCMS (ESI) m/e 481.1 [(M+Na)⁺, calcdC₂₅H₃₉BN₂NaO₅, 481.3]; LC/MS retention time (method B): t_(R)=2.49 min.

Part C: (S)-tert-butyl(1-(4-(2-chloro-3-fluoropyridin-4-yl)-2-cyanophenoxy)-2,4-dimethylpentan-2-yl)carbamate

A mixture of 2-chloro-3-fluoro-4-iodopyridine (105 mg, 0.408 mmol),(S)-tert-butyl(1-(2-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate(374 mg, 0.816 mmol), potassium carbonate (169 mg, 1.224 mmol), andPd(Ph₃P)₄ (14.14 mg, 0.012 mmol) in toluene (1 mL), water (0.050 mL),and ethanol (0.100 mL) in a pressure rated 1 dram vial was purged ofoxygen, and stirred under nitrogen at 80° C. overnight. The mixture wasfiltered via syringe tip filter and concentrated under reduced pressure.The residue was purified by silica gel chromatography (10-80% ethylacetate/hexanes gradient elution) to afford (S)-tert-butyl(1-(4-(2-chloro-3-fluoropyridin-4-yl)-2-cyanophenoxy)-2,4-dimethylpentan-2-yl)carbamate(49 mg, 0.106 mmol, 26% yield) as a light yellow film. LCMS (ESI) m/e462.0 (M+H)⁺, calcd C₂₃H₃₀ClFN₃O₃, 462.2]; LC/MS retention time (methodD): t_(R)=1.30 min; ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.28 (d, J=5.0 Hz,1H), 7.82 (dd, J=2.0, 1.0 Hz, 1H), 7.77 (dt, J=8.8, 1.9 Hz, 1H),7.33-7.29 (m, 1H), 7.18 (d, J=9.0 Hz, 1H), 4.59 (s, 1H), 4.45 (d, J=8.8Hz, 1H), 4.22 (d, J=9.0 Hz, 1H), 2.01-1.92 (m, 1H), 1.91-1.79 (m, 1H),1.56-1.50 (m, 1H), 1.46 (s, 3H), 1.40 (s, 9H), 1.03 (d, J=6.8 Hz, 6H).

Part D: (S)-methyl(4-(4-((2-Boc-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)-3-fluoropyridin-2-yl)carbamate

A solution of (S)-tert-butyl(1-(4-(2-amino-3-fluoropyridin-4-yl)-2-cyanophenoxy)-2,4-dimethylpentan-2-yl)carbamate(40 mg, 0.090 mmol) cooled to 0° C. was added methyl chloroformate(0.035 mL, 0.452 mmol) and pyridine (0.073 mL, 0.904 mmol) followed byDMAP (1.104 mg, 9.04 μmol). The cooling bath was removed and the mixturestirred overnight. The reaction mixture was concentrated under reducedpressure. Obtained (S)-methyl(4-(4-((2-Boc-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)-3-fluoropyridin-2-yl)carbamate(20 mg, 0.040 mmol, 44% crude yield) which was used without furtherpurification. LCMS (ESI) m/e 501.1 (M+H)⁺, calcd C₂₃H₃₀ClFN₃O₃, 501.3];LC/MS retention time (method D): t_(R)=1.17 min.

Part E: (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)-3-fluoropyridin-2-yl)carbamate

(S)-Methyl(4-(4-((2-Boc-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)-3-fluoropyridin-2-yl)carbamate(20 mg, 0.040 mmol) and TFA (1 mL, 12.98 mmol) were stored at ambienttemperature for 2 hours. The resultant was concentrated under reducedpressure. The residue was purified via preparative LC/MS (Column:XBridge C18, 19×200 mm, 5-am; Mobile Phase A: 5:95 acetonitrile: waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: waterwith 10-mM ammonium acetate; Gradient: 45-85% B over 15 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min.). Obtained (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)-3-fluoropyridin-2-yl)carbamate(4.1 mg, 10.14 □mol, 25% yield for two steps) as a colorless solid. LCMS(ESI) m/e 401.0 (M+H)⁺, calcd C₂₁H₂₆FN₄O₃, 401.2]; LC/MS retention time(method D): t_(R)=0.82 min; ¹H NMR (500 MHz, DMSO-d₆) δ 8.26 (d, J=4.8Hz, 1H), 8.05 (s, 1H), 7.95 (d, J=9.5 Hz, 1H), 7.50 (t, J=5.1 Hz, 1H),7.43 (d, J=8.8 Hz, 1H), 4.13-3.99 (m, 2H), 1.91 (s, 3H), 1.86-1.78 (m,1H), 1.60-1.44 (m, 2H), 1.24 (s, 3H), 0.94 (t, J=5.9 Hz, 6H).

Example 101(S)-6-((2-amino-2,4-dimethylpentyl)oxy)-2′-methyl-[3,4′-bipyridine]-5-carbonitrile

Prepared as described in Example 32 to afford(S)-6-((2-amino-2,4-dimethylpentyl)oxy)-2′-methyl-[3,4′-bipyridine]-5-carbonitrile(16 mg, 0.054 mmol, 44% yield for the final step) as a pale yellow oil.LCMS (ESI) m/e 325.1 [(M+H)⁺, calcd C₁₉H₂₅N₄O, 325.2]; LC/MS retentiontime (method D): t_(R)=0.58 min; ¹H NMR (500 MHz, DMSO-d₆) δ 9.02 (d,J=2.2 Hz, 1H), 8.92 (d, J=2.6 Hz, 1H), 8.68 (d, J=5.5 Hz, 1H), 8.42 (br.s., 2H), 7.99 (s, 1H), 7.89 (d, J=4.8 Hz, 1H), 4.74-4.47 (m, 2H), 2.64(s, 3H), 1.89 (dt, J=12.6, 6.4 Hz, 1H), 1.83-1.74 (m, 1H), 1.65 (dd,J=14.3, 5.5 Hz, 1H), 1.43 (s, 3H), 0.98 (d, J=1.8 Hz, 3H), 0.96 (d,J=1.8 Hz, 3H).

Example 102(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(7-methylquinolin-4-yl)benzonitrile

Prepared as described in Example 32 to afford(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(7-methylquinolin-4-yl)benzonitrile(76 mg, 0.195 mmol, 53% yield for the final step) as a colorless film.LCMS (ESI) m/e 374.0 [(M+H)⁺, calcd C₂₄H₂₈N₃O, 374.2]; LC/MS retentiontime (method D): t_(R)=0.76 min; ¹H NMR (600 MHz, DMSO-d₆) δ 8.90 (d,J=4.0 Hz, 1H), 7.98 (s, 1H), 7.91 (s, 1H), 7.87 (dd, J=8.8, 2.2 Hz, 1H),7.73 (d, J=8.4 Hz, 1H), 7.48 (dd, J=8.1, 4.8 Hz, 2H), 7.42 (d, J=4.0 Hz,1H), 4.29-4.09 (m, 2H), 2.55 (s, 3H), 1.86 (dt, J=12.3, 6.3 Hz, 1H),1.72 (dd, J=13.9, 5.1 Hz, 1H), 1.58 (dd, J=14.1, 5.7 Hz, 1H), 1.35 (s,3H), 0.97 (t, J=6.2 Hz, 6H).

Example 103(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(3-fluoro-2-methylpyridin-4-yl)benzonitrile

Prepared as described in Example 32 to afford(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(3-fluoro-2-methylpyridin-4-yl)benzonitrile(7.7 mg, 0.022 mmol, 74% yield for the final step) as a colorless film.LCMS (ESI) m/e 342.0 [(M+H)⁺, calcd C₂₀H₂₅FN₃O, 342.2]; LC/MS retentiontime (method D): t_(R)=0.79 min; ¹H NMR (600 MHz, DMSO-d₆) δ 8.35 (d,J=4.8 Hz, 1H), 8.05 (s, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.48 (br. s., 1H),7.39 (d, J=8.8 Hz, 1H), 3.96-3.83 (m, 2H), 2.51 (s, 3H), 1.82 (dt,J=12.1, 6.1 Hz, 1H), 1.52-1.37 (m, 2H), 1.15 (s, 3H), 0.93 (t, J=5.0 Hz,6H).

Example 104(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(quinolin-4-yl)benzonitrile

Prepared as described in Example 32 to afford(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(quinolin-4-yl)benzonitrile(23 mg, 0.061 mmol, 14% yield for the final step) as a colorless film.LCMS (ESI) m/e 360.0 [(M+H)⁺, calcd C₂₃H₂₆N₃O, 360.2]; LC/MS retentiontime (method D): t_(R)=0.69 min; ¹H NMR (600 MHz, DMSO-d₆) δ 8.97 (d,J=4.4 Hz, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.90-7.79 (m, 3H),7.64 (t, J=7.2 Hz, 1H), 7.50 (d, J=4.4 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H),4.11-3.98 (m, 2H), 1.86 (dquin, J=12.5, 6.4 Hz, 1H), 1.63-1.45 (m, 2H),1.25 (s, 3H), 0.97 (t, J=6.2 Hz, 6H).

Example 105(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(5-fluoro-2-methylpyridin-4-yl)benzonitrile

Prepared as described in Example 32 to afford(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(5-fluoro-2-methylpyridin-4-yl)benzonitrile(9.5 mg, 0.026 mmol, 25% yield for the final step) as a pale yellowfilm. LCMS (ESI) m/e 342.0 [(M+H)⁺, calcd C₂₀H₂₅FN₃O, 342.2]; LC/MSretention time (method D): t_(R)=0.80 min; ¹H NMR (500 MHz, DMSO-d₆) δ8.50 (d, J=2.6 Hz, 1H), 8.08 (d, J=1.8 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H),7.56 (d, J=6.6 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 3.96-3.85 (m, 2H), 2.52(s, 3H), 1.86-1.77 (m, 1H), 1.51-1.36 (m, 2H), 1.15 (s, 3H), 0.94 (d,J=3.7 Hz, 3H), 0.93 (d, J=3.7 Hz, 3H).

Example 106(S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)-5-fluoropyridin-2-yl)carbamate

Prepared as described in Example 100 to afford (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)-5-fluoropyridin-2-yl)carbamate(20.5 mg, 0.050 mmol, 36% yield for the final step) as a colorless film.LCMS (ESI) m/e 401.0 (M+H)⁺, calcd C₂₁H₂₆FN₄O₃, 401.2]; LC/MS retentiontime (method D): t_(R)=0.91 min; ¹H NMR (500 MHz, DMSO-d₆) δ 8.38 (s,1H), 8.02 (s, 1H), 7.97 (d, J=5.9 Hz, 1H), 7.91 (d, J=9.2 Hz, 1H), 7.41(d, J=8.8 Hz, 1H), 3.96-3.84 (m, 2H), 2.52 (s, 3H), 1.82 (dt, J=12.7,6.3 Hz, 1H), 1.49-1.34 (m, 2H), 1.15 (s, 3H), 0.94 (d, J=3.7 Hz, 3H),0.93 (d, J=3.7 Hz, 3H).

Example 107(S)-1-((6-fluoro-2′,4-dimethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (6-chloro-2-fluoropyridin-3-yl)boronic acid

A solution of LDA (1M in THF) (8.36 ml, 8.36 mmol) at −78° C. wastreated dropwise with a solution of 2-chloro-6-fluoropyridine (1.0 g,7.60 mmol) in THE (2 mL). The mixture was maintained at −78° C. for 1 hand then treated with a solution of triisopropyl borate (1.765 ml, 7.60mmol) in THE (1 mL). The reaction mixture was treated with water (4 mL)and concentrated under reduced pressure to afford(6-chloro-2-fluoropyridin-3-yl)boronic acid (1.33 g, 7.60 mmol, 100%crude yield) as a pale orange waxy solid that was used without furtherpurification. LCMS (ESI) m/e 176.0 (M+H)⁺, calcd C₅H₅BClFNO₂, 176.0];LC/MS retention time (method D): t_(R)=0.71 min.

Part B: 6-chloro-2-fluoropyridin-3-ol

A suspension of (6-chloro-2-fluoropyridin-3-yl)boronic acid (1.3 g, 7.41mmol) in NaOH (4.45 ml, 22.24 mmol) at 0° C. was treated all at oncewith hydrogen peroxide (0.500 ml, 8.15 mmol). The mixture was stirred atambient temperature overnight. The resulting solution was quenched withice water, acidified with 3 N aqueous hydrochloric acid to pH=5, andextracted three times with ethyl acetate. The pooled organics were driedover sodium sulfate and concentrated under reduced pressure to afford6-chloro-2-fluoropyridin-3-ol (1.08 g, 7.32 mmol, 99% crude yield) as awaxy solid that was used without further purification. LCMS (ESI) m/e148.0 (M+H)⁺, calcd C₅H₄ClFNO, 148.0]; LC/MS retention time (method D):t_(R)=0.83 min.

Part C: 6-chloro-2-fluoro-3-(methoxymethoxy)pyridine

A solution of 6-chloro-2-fluoropyridin-3-ol (0.49 g, 3.32 mmol), MOM-Cl(0.277 mL, 3.65 mmol), potassium carbonate (0.551 g, 3.99 mmol) inacetone (20 mL) was stirred at 60° C. for 3 h. The mixture was cooled toambient temperature and vacuum filtered. The filtrate was concentratedunder reduced pressure. The residue was purified by silica gelchromatography (5-30% ethyl acetate/hexanes) to afford6-chloro-2-fluoro-3-(methoxymethoxy)pyridine (0.24 g, 1.25 mmol, 38%yield for three steps) as a near colorless oil. LCMS (ESI) m/e 192.0(M+H)⁺, calcd C₇H₈ClFNO₂, 192.0]; LC/MS retention time (method D):t_(R)=1.20 min; ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.57 (dd, J=9.8, 8.3Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 5.24 (s, 2H), 3.56-3.52 (m, 3H).

Part D: 6-chloro-2-fluoro-3-(methoxymethoxy)-4-methylpyridine

A solution of 6-chloro-2-fluoro-3-(methoxymethoxy)pyridine (0.24 g,1.253 mmol) in tetrahydrofuran (9 mL) at −78° C. was treated dropwisewith LDA (1.378 mL, 1.378 mmol). The resulting orange solution wasmaintained at −78° C. for 1 h and then treated dropwise with a solutionof methyl iodide (0.094 mL, 1.503 mmol) in THE (0.5 mL). The resultingsolution was stirred at −78° C. for 30 min. The resulting solution waswarmed to ambient temperature, quenched with saturated aqueous ammoniumchloride (5 mL), and stirred overnight. The layers were separated andthe aqueous layer was extracted with ethyl acetate. The pooled organicswere dried over sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel chromatography (5-30% ethylacetate/hexanes) afforded6-chloro-2-fluoro-3-(methoxymethoxy)-4-methylpyridine (0.22 g, 1.07mmol, 85% yield) as a colorless oil. LCMS (ESI) m/e 206.1 (M+H)⁺, calcdC₈H₁₀ClFNO₂, 206.0]; LC/MS retention time (method D): t_(R)=1.05 min; ¹HNMR (400 MHz, CHLOROFORM-d) δ 7.07 (s, 1H), 5.21-5.10 (m, 2H), 3.64-3.54(m, 3H), 2.37 (d, J=1.0 Hz, 3H).

Part E: 6-fluoro-5-(methoxymethoxy)-2′,4-dimethyl-2,4′-bipyridine

To a pressure rated vial was added6-chloro-2-fluoro-3-(methoxymethoxy)-4-methylpyridine (110 mg, 0.535mmol), (2-methylpyridin-4-yl)boronic acid (81 mg, 0.588 mmol), cesiumcarbonate (349 mg, 1.070 mmol), toluene (1 mL), and ethanol (0.200 mL).The solution was sparged with a stream of nitrogen for 5 min.Tetrakis(triphenylphosphine)palladium(0) (43.3 mg, 0.037 mmol) was addedand the vial was sealed, purged of oxygen, and stirred under nitrogen at85° C. overnight. The resulting suspension was vacuum filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (5-40% ethyl acetate/hexanes gradient elution) toafford 6-fluoro-5-(methoxymethoxy)-2′,4-dimethyl-2,4′-bipyridine (40 mg,0.153 mmol, 29% yield) as a near colorless oil. LCMS (ESI) m/e 263.1(M+H)⁺, calcd C₁₄H₁₆FN₂O₂, 263.1]; LC/MS retention time (method D):t_(R)=0.80 min; ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.59 (d, J=5.3 Hz, 1H),7.73 (s, 1H), 7.61 (dd, J=5.3, 1.3 Hz, 1H), 7.55 (s, 1H), 5.24 (d, J=1.0Hz, 2H), 3.63 (s, 3H), 2.65 (s, 3H), 2.47 (s, 3H).

Part F: 6-fluoro-2′,4-dimethyl-[2,4′-bipyridin]-5-ol

A solution of 6-fluoro-5-(methoxymethoxy)-2′,4-dimethyl-2,4′-bipyridine(40 mg, 0.153 mmol) in methanol (5 mL) and HCl (conc.) (0.05 mL, 0.600mmol) was stirred at 65° C. for 1 h and then concentrated under reducedpressure to afford 6-fluoro-2′,4-dimethyl-[2,4′-bipyridin]-5-ol (30 mg,0.137 mmol, 90% yield) as a pale tan solid. Used without furtherpurification. LCMS (ESI) m/e 219.1 (M+H)⁺, calcd C₁₂H₁₂FN₂O, 219.1];LC/MS retention time (method D): t_(R)=0.59 min.

Part G: (S)-tert-butyl(1-((6-fluoro-2′,4-dimethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

A solution of 6-fluoro-2′,4-dimethyl-[2,4′-bipyridin]-5-ol (30 mg, 0.137mmol), (S)-tert-butyl4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(48.4 mg, 0.165 mmol), and cesium carbonate (134 mg, 0.412 mmol) inN,N-dimethylformamide (1 mL) in a pressure rated vial was stirred at 80°C. overnight. The mixture was cooled to ambient temperature and filteredthrough a syringe tip filter. Obtained (S)-tert-butyl(1-((6-fluoro-2′,4-dimethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(38.6 mg, 0.089 mmol, 65% crude yield) as a colorless oil that was usedwithout further purification. LCMS (ESI) m/e 432.2 (M+H)⁺, calcdC₂₄H₃₅FN₃O₃, 432.3]; LC/MS retention time (method D): t_(R)=1.08 min.

Part H:(S)-1-((6-fluoro-2′,4-dimethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

A solution of (S)-tert-butyl(1-((6-fluoro-2′,4-dimethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(38 mg, 0.088 mmol) in DMF (1 mL) was treated with TFA (1 mL, 12.98mmol) and stirred at ambient temperature overnight. The solution wasconcentrated under reduced pressure. The crude material was purified viapreparative LC/MS (Column: XBridge C18, 19×200 mm, 5-μm; Mobile Phase A:5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 20-60% Bover 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min).Obtained(S)-1-((6-fluoro-2′,4-dimethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(20 mg, 0.060 mmol, 68% crude yield) as a colorless oil that was usedwithout further purification. LCMS (ESI) m/e 332.3 (M+H)⁺, calcdC₁₉H₂₇FN₃O, 332.2]; LC/MS retention time (method D): t_(R)=0.64 min; ¹HNMR (500 MHz, DMSO-d₆) δ 8.54 (d, J=5.1 Hz, 1H), 7.99 (s, 1H), 7.83 (s,1H), 7.74 (d, J=4.4 Hz, 1H), 3.84-3.80 (m, 2H), 2.55 (s, 3H), 2.41 (s,3H), 1.88-1.75 (m, 1H), 1.49-1.31 (m, 2H), 1.15 (s, 3H), 1.00-0.90 (m,6H).

Example 108 methyl(5-((3-isobutylazetidin-3-yl)methoxy)-6-methyl-[2,4′-bipyridin]-2′-yl)carbamate

Part A: 1-tert-butyl 3-methyl 3-isobutylazetidine-1,3-dicarboxylate

A solution of 1-tert-butyl 3-methyl azetidine-1,3-dicarboxylate (5.0 g,23.23 mmol) and 1-iodo-2-methylpropane (21.37 g, 116 mmol) intetrahydrofuran (100 mL) at −78° C. was treated dropwise with KHMDS(69.7 mL, 34.8 mmol). The solution was stirred at ambient temperatureovernight. The resulting suspension was diluted with ethyl acetate (500mL), washed with 0.5 N aqueous hydrochloric acid (2×100 mL), and brine(1×100 mL), dried over sodium sulfate and concentrated. The residue waspurified via silica gel chromatography purification (2-20% ethylacetate/hexanes gradient elution) to afford 1-tert-butyl 3-methyl3-isobutylazetidine-1,3-dicarboxylate (3.37 g, 12.42 mmol, 54% yield) asan amber oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ 4.22 (d, J=8.8 Hz, 2H),3.82-3.70 (m, 5H), 1.87 (d, J=7.0 Hz, 2H), 1.63-1.51 (m, 1H), 1.45 (s,9H), 0.89 (d, J=6.8 Hz, 6H).

Part B: tert-butyl 3-isobutyl-3-(methoxymethyl)azetidine-1-carboxylate

A solution of 1-tert-butyl 3-methyl3-isobutylazetidine-1,3-dicarboxylate (2.51 g, 9.25 mmol) intetrahydrofuran (40 mL) at ambient temperature was treated with lithiumborohydride (0.403 g, 18.50 mmol) and stirred at 70° C. for 3 h. TLCindicated 50% consumption of starting material. The reaction mixture wastreated with additional lithium borohydride (0.302 g, 13.97 mmol) andstirred for 1.5 h at 70° C. TLC indicated complete consumption ofstarting material. The reaction mixture was cooled to 0° C., quenchedwith 0.1N aqueous hydrochloric acid, and then diluted with ethylacetate. The layers were separated and the aqueous extracted with ethylacetate (2×). The pooled organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (10-80% ethyl acetate/hexanesgradient elution) to afford tert-butyl3-isobutyl-3-(methoxymethyl)azetidine-1-carboxylate (2.07 g, 8.51 mmol,92% yield) as a colorless oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ3.81-3.70 (m, 4H), 3.64 (d, J=8.5 Hz, 2H), 1.74 (tt, J=13.5, 6.7 Hz,2H), 1.60 (d, J=7.0 Hz, 2H), 1.46 (s, 9H), 0.91 (d, J=6.5 Hz, 6H).

Part C: tert-butyl3-(((6-bromo-2-methylpyridin-3-yl)oxy)methyl)-3-isobutylazetidine-1-carboxylate

A solution of tert-butyl3-(hydroxymethyl)-3-isobutylazetidine-1-carboxylate (0.582 g, 2.392mmol) in tetrahydrofuran (4 mL) was charged to a pressure rated vial andtreated dropwise with KOtBu (1M in THF) (2.392 mL, 2.392 mmol). After 5minutes, 6-bromo-3-fluoro-2-methylpyridine (0.50 g, 2.63 mmol) in THF (2mL) was added all at once. The vial was sealed and heated to 80° C.overnight. The mixture was partitioned between ethyl acetate and brine.The layers were separated and the aqueous extracted with ethyl acetate(2×). The pooled organics were dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified via silicagel chromatography to afford tert-butyl3-(((6-bromo-2-methylpyridin-3-yl)oxy)methyl)-3-isobutylazetidine-1-carboxylate(50 mg, 0.121 mmol, 5% yield) as a near colorless oil. LCMS (ESI) m/e313.0 (M-Boc+H)⁺, calcd C₁₄H₂₂BrN₂O, 313.1]; LC/MS retention time(method D): t_(R)=0.92 min.

Part D: tert-butyl3-isobutyl-3-(((2′-((methoxycarbonyl)amino)-6-methyl-[2,4′-bipyridin]-5-yl)oxy)methyl)azetidine-1-carboxylate

A solution of (2-((methoxycarbonyl)amino)pyridin-4-yl)boronic acid (50mg, 0.255 mmol), tert-butyl3-(((6-bromo-2-methylpyridin-3-yl)oxy)methyl)-3-isobutylazetidine-1-carboxylate(70.3 mg, 0.170 mmol), Pd(Ph₃P)₄ (13.76 mg, 0.012 mmol), and cesiumcarbonate (111 mg, 0.340 mmol) in toluene (1 mL), and ethanol (0.1 mL)was charged to a pressure rated vial and sparged with a stream ofnitrogen for 5 min. The vial was sealed, purged of oxygen, and stirredunder nitrogen at 80° C. overnight. The mixture was cooled to ambienttemperature and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (10-80% ethyl acetate/hexanesgradient elution) to afford tert-butyl3-isobutyl-3-(((2′-((methoxycarbonyl)amino)-6-methyl-[2,4′-bipyridin]-5-yl)oxy)methyl)azetidine-1-carboxylate(29 mg, 0.060 mmol, 35% yield) as a pale yellow film. LCMS (ESI) m/e485.1 (M+H)⁺, calcd C₂₆H₃₇N₄O₅, 485.3]; LC/MS retention time (method D):t_(R)=1.14 min.

Part D: methyl(5-((3-isobutylazetidin-3-yl)methoxy)-6-methyl-[2,4′-bipyridin]-2′-yl)carbamate

Tert-butyl3-isobutyl-3-(((2′-((methoxycarbonyl)amino)-6-methyl-[2,4′-bipyridin]-5-yl)oxy)methyl)azetidine-1-carboxylate(29 mg, 0.060 mmol) and TFA (1 mL, 12.98 mmol) were stirred at ambienttemperature for 3 h. The solution was concentrated under reducedpressure. The crude material was purified via preparative HPLC (Column:XBridge C18, 19×200 mm, 5-am; Mobile Phase A: 5:95 methanol: water with10-mM ammonium acetate; Mobile Phase B: 95:5 methanol: water with 10-mMammonium acetate; Gradient: 40-80% B over 40 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min). Obtained methyl(5-((3-isobutylazetidin-3-yl)methoxy)-6-methyl-[2,4′-bipyridin]-2′-yl)carbamate(11.5 mg, 0.030 mmol, 50% yield) as a colorless film. LCMS (ESI) m/e385.1 (M+H)⁺, calcd C₂₁H₂₉N₄O₃, 385.3]; LC/MS retention time (method D):t_(R)=0.76 min; ¹H NMR (500 MHz, DMSO-d₆) δ 8.49 (s, 1H), 8.31 (d, J=5.1Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.64 (d, J=4.4 Hz, 1H), 7.56 (d, J=8.4Hz, 1H), 4.27 (s, 2H), 3.54-3.38 (m, 4H), 2.46 (s, 3H), 1.86 (m, 3H),1.73-1.59 (m, 3H), 0.86 (d, J=5.9 Hz, 6H).

Example 109(S)-2-((2-amino-4-methylpentyl)oxy)-5-(6-methylpyridazin-4-yl)benzonitrile

Part A: (S)-tert-butyl(1-(2-cyano-4-(6-methylpyridazin-4-yl)phenoxy)-4-methylpentan-2-yl)carbamate

To a 2 mL vial was added (6-methylpyridazin-4-yl)boronic acid (20.56 mg,0.149 mmol), (S)-tert-butyl(1-(4-bromo-2-cyanophenoxy)-4-methylpentan-2-yl)carbamate (42.3 mg,0.106 mmol), and Na₂CO₃ (0.160 mL, 0.319 mmol) in dioxane (0.5 mL) togive a colorless suspension under nitrogen.1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, toluene(4.38 mg, 5.32 μmol) was added under nitrogen. The vial was sealed andheated at 100° C. (bath: 108° C.) for 2 h. The mixture was diluted withEtOAc, dried with Na₂SO₄, and passed through a plug of Na₂SO₄. Theorganic solution was concentrated to afford the desired product (70 mg,100% crude yield) as a tan oil, which was directly used in the nextstep. LCMS (ESI) m/e 411.2 [(M+H)⁺, calcd C₂₃H₃₁N₄O₃, 411.2].

Part B:(S)-2-((2-amino-4-methylpentyl)oxy)-5-(6-methylpyridazin-4-yl)benzonitrile

Prepared as previously described in Example 7, Part B to afford(S)-2-((2-amino-4-methylpentyl)oxy)-5-(6-methylpyridazin-4-yl)benzonitrile(20.8 mg, 63% for 2 steps) as a colorless solid. ¹H NMR (500 MHz,DMSO-d₆) δ 9.51 (d, J=2.4 Hz, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.24 (dd,J=8.9, 2.5 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.44 (d, J=9.0 Hz, 1H), 4.11(dd, J=9.7, 5.1 Hz, 1H), 4.04 (dd, J=9.6, 6.3 Hz, 1H), 3.17 (t, J=6.6Hz, 1H), 2.67 (s, 3H), 1.84 (p, J=6.6 Hz, 1H), 1.38 (ddd, J=13.5, 8.3,5.0 Hz, 1H), 1.30 (dq, J=13.9, 7.0, 6.4 Hz, 1H), 0.93 (d, J=6.6 Hz, 3H),0.89 (d, J=6.6 Hz, 3H); LCMS (ESI) m/e 311.2 [(M+H)⁺, calcd C₁₈H₂₃N₄O,311.2]; LC/MS retention time (method B): t_(R)=1.46 min.

Example 110(S)-1-(2-(isoxazol-5-yl)-4-(quinolin-4-yl)phenoxy)-4-methylpentan-2-amine

Part A: (S)-tert-butyl(1-(4-bromo-2-(isoxazol-5-yl)phenoxy)-4-methylpentan-2-yl)carbamate

To a 15 mL vial was added (S)-tert-butyl(1-hydroxy-4-methylpentan-2-yl)carbamate (204 mg, 0.939 mmol), Ph₃P (320mg, 1.220 mmol), and 4-bromo-2-(isoxazol-5-yl)phenol (225 mg, 0.939mmol) in tetrahydrofuran (3 mL) to give a tan solution. DIAD (0.256 mL,1.314 mmol) was added at rt. The resultant clear tan solution wasstirred at rt overnight for 18 h. The solution was concentrated to adense oil and was directly purified by silica gel chromatography (up to40% EtOAc/hexane) to afford (S)-tert-butyl(1-(4-bromo-2-(isoxazol-5-yl)phenoxy)-4-methylpentan-2-yl)carbamate (319mg, 77%) as a white solid: ¹H NMR (400 MHz, Chloroform-d) δ 8.31 (s,1H), 8.09 (d, J=2.4 Hz, 1H), 7.46 (dd, J=9.1, 2.6 Hz, 1H), 6.88 (d,J=9.0 Hz, 2H), 4.60 (d, J=8.9 Hz, 1H), 4.19 (d, J=7.0 Hz, 1H), 4.02 (qd,J=9.2, 5.2 Hz, 2H), 1.75 (dq, J=13.6, 6.7 Hz, 1H), 1.46 (d, J=12.0 Hz,11H), 0.98 (d, J=6.6 Hz, 6H).

Part B: (S)-tert-butyl(1-(2-(isoxazol-5-yl)-4-(quinolin-4-yl)phenoxy)-4-methylpentan-2-yl)carbamate

Prepared as previously described in Example 109 to afford (S)-tert-butyl(1-(2-(isoxazol-5-yl)-4-(quinolin-4-yl)phenoxy)-4-methylpentan-2-yl)carbamate.LCMS (ESI) m/e 488.4 [(M+H)⁺, calcd C₂₉H₃₄N₃O₄, 488.2]; LC/MS retentiontime (method A): t_(R)=2.27 min.

Part C:(S)-1-(2-(isoxazol-5-yl)-4-(quinolin-4-yl)phenoxy)-4-methylpentan-2-amine

Prepared as previously described in Example 7, Part B to afford(S)-1-(2-(isoxazol-5-yl)-4-(quinolin-4-yl)phenoxy)-4-methylpentan-2-amine(12.9 mg, 44% for two steps): ¹H NMR (500 MHz, DMSO-d₆) δ 8.97 (d, J=4.4Hz, 1H), 8.72 (d, J=1.8 Hz, 1H), 8.14 (d, J=8.5 Hz, 1H), 8.02 (d, J=2.3Hz, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.70 (dd,J=8.5, 2.3 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.54 (d, J=4.4 Hz, 1H), 7.45(d, J=8.6 Hz, 1H), 7.06 (d, J=1.9 Hz, 1H), 4.13 (dd, J=9.4, 4.9 Hz, 1H),4.05 (dd, J=9.4, 6.2 Hz, 1H), 3.25 (dq, J=10.4, 5.6 Hz, 1H), 1.85 (dt,J=13.4, 7.5 Hz, 1H), 1.41 (ddd, J=13.4, 8.4, 4.7 Hz, 1H), 1.32 (ddd,J=13.8, 8.7, 5.6 Hz, 1H), 0.93 (dd, J=9.2, 6.6 Hz, 6H); LCMS (ESI) m/e388.1 [(M+H)⁺, calcd C₂₄H₂₆N₃O₂, 388.2]; LC/MS retention time (methodB): t_(R)=1.59 min.

Example 111(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-2-methylnicotinicacid

Part A: (3-(methoxycarbonyl)-2-methylpyridin-4-yl)boronic acid

To a vial was added methyl 4-chloro-2-methylnicotinate (52 mg, 0.280mmol), hypodiboric acid (37.7 mg, 0.420 mmol),2-(dicyclohexylphosphino))-2′,4′,6′-triisopropylbiphenyl (2.67 mg, 5.60μmol), Xphos precatalyst (2.204 mg, 2.80 μmol) and potassium acetate (82mg, 0.840 mmol) in ethanol (2.6 mL) to give a tan suspension (degassedbefore adding reagents). The vial was capped and heated at 80° C. for 1h. LCMS showed conversion of the starting material to a new polar peakbut with no parent ion. The mixture was directly used in the next step.

Part B:(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-2-methylnicotinicacid

To a 20 mL vial was added(3-(methoxycarbonyl)-2-methylpyridin-4-yl)boronic acid (48.9 mg, 0.251mmol) (previous reaction vessel) was added potassium phosphate tribasic(2.2 mL, 1.100 mmol). After degassing for 5 min, Xphos precatalyst (4.5mg, 5.72 μmol) and(S)-1-(4-bromo-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(33 mg, 0.084 mmol) and tetrahydrofuran (2.2 mL) were added. The vialwas sealed and heated at 80° C. overnight for 18 h. Volatiles were blownoff. The residue was partitioned between EtOAc and water. The organiclayer was dried, filtered and concentrated. The residue was dissolved inMeOH and purified by prep-HPLC to afford(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-2-methylnicotinicacid (18.8 mg, 53%): ¹H NMR (600 MHz, DMSO-d₆) δ 8.27 (d, J=5.1 Hz, 1H),7.88 (s, 1H), 7.83 (d, J=8.6 Hz, 1H), 7.08 (d, J=5.2 Hz, 1H), 6.96 (d,J=8.6 Hz, 1H), 3.99-3.92 (m, 2H), 2.47 (s, 3H), 1.88-1.72 (m, 1H),1.60-1.45 (m, 2H), 1.24 (s, 3H), 0.89 (d, J=6.5 Hz, 6H); LCMS (ESI) m/e433.2 [(M+Na)⁺, calcd C₂₁H₂₅F₃N₂O₃Na, 433.2]; LC/MS retention time(method C): t_(R)=2.60 min.

Example 112(S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-((dimethylamino)methyl)phenyl)pyridin-2-yl)carbamate

Part A: (S)-methyl(4-(4-((2-Boc-amino-2,4-dimethylpentyl)oxy)-3-((dimethylamino)methyl)phenyl)pyridin-2-yl)carbamate

To a 2 mL vial was added crude aldehyde (prepared as described inExample 32 (10.68 mg, 0.022 mmol) in CH₂Cl₂ (0.5 mL) to give a tansolution. Dimethylamine (0.110 mL, 0.220 mmol) (2.0 M in THF, excess)was added, followed by sodium triacetoxyborohydride (0.019 g, 0.088mmol). The mixture was stirred at rt overnight for 16 h. LCMS showedcomplete conversion to the desired product (M+H=515.2). The mixture waspartitioned between water and EtOAc. The layers were separated. Theorganic layer was washed with brine, dried and concentrated. The tanresidue was directly carried onto next reaction.

Part B: (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-((dimethylamino)methyl)phenyl)pyridin-2-yl)carbamate

Prepared as previously described in Example 7, Part B to afford(S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-((dimethylamino)methyl)phenyl)pyridin-2-yl)carbamate(5.5 mg, 60% for three steps): ¹H NMR (500 MHz, DMSO-d₆) δ 8.28 (d,J=5.3 Hz, 1H), 8.10 (s, 1H), 7.64 (d, J=6.8 Hz, 2H), 7.32 (d, J=5.4 Hz,1H), 7.12 (d, J=8.8 Hz, 1H), 3.83 (s, 2H), 3.70 (s, 3H), 3.51 (s, 2H),2.20 (s, 6H), 1.81 (dt, J=12.6, 6.4 Hz, 1H), 1.46 (qd, J=14.0, 5.6 Hz,2H), 1.19 (s, 3H), 0.94 (t, J=6.1 Hz, 6H); LCMS (ESI) m/e 415.1 [(M+H)⁺,calcd C₂₃H₃₅N₄O₃, 415.3]; LC/MS retention time (method B): t_(R)=1.43min.

Example 113(S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(methylsulfonyl)phenyl)pyridin-2-yl)carbamate

Part A:(S)-1-(4-bromo-2-(methylsulfonyl)phenoxy)-2,4-dimethylpentan-2-amine

To a 5 mL vial was added (S)-2-amino-2,4-dimethylpentan-1-ol (120 mg,0.915 mmol) in tetrahydrofuran (1.2 mL) to give a colorless solution.Potassium tert-butoxide (1.097 mL, 1.097 mmol) (1.0 M in THF) was addeddropwise under nitrogen. After 5 min,4-bromo-1-fluoro-2-(methylsulfonyl)benzene (243 mg, 0.960 mmol) wasadded in one portion. The bottle was sealed and the mixture was stirredat 70° C. for 18 h. The mixture was partitioned between water and EtOAc.The layers were separated. The aqueous layer was extracted with EtOAc.The combined organic solution was washed with brine, dried andconcentrated to a red oil (313 mg, 94%): ¹H NMR (400 MHz, Chloroform-d)δ 8.10 (d, J=2.6 Hz, 1H), 7.69 (dd, J=8.8, 2.5 Hz, 1H), 6.94 (d, J=8.8Hz, 1H), 3.90 (q, J=8.5 Hz, 2H), 3.24 (s, 3H), 1.90-1.75 (m, 1H), 1.52(dd, J=5.7, 3.5 Hz, 2H), 1.28 (s, 3H), 1.01 (dd, J=10.6, 6.7 Hz, 6H);LCMS (ESI) m/e 363.9 [(M+H)⁺, calcd C14H23BrNO₃S, 364.1]; LC/MSretention time (method B): t_(R)=1.64 min.

Part B: (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(methylsulfonyl)phenyl)pyridin-2-yl)carbamate

Prepared as previously described in Example 109 to afford (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(methylsulfonyl)phenyl)pyridin-2-yl)carbamate(25.6 mg, 75%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.34 (d, J=5.2 Hz, 1H), 8.14(s, 1H), 8.12-8.03 (m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.38 (d, J=5.3 Hz,1H), 3.97 (s, 2H), 3.71 (s, 3H), 3.42 (s, 3H), 1.83 (dt, J=12.2, 6.2 Hz,1H), 1.49-1.37 (m, 2H), 1.17 (s, 3H), 0.94 (dd, J=8.7, 6.6 Hz, 6H); LCMS(ESI) m/e 436.0 [(M+H)⁺, calcd C₂₁H₃N₃O₅S, 436.2]; LC/MS retention time(method B): t_(R)=1.52 min.

Example 114(S)-2,4-dimethyl-1-(4-(2-methylpyridin-4-yl)-2-(methylsulfonyl)phenoxy)pentan-2-amine

Prepared as described in Example 113 to afford(S)-2,4-dimethyl-1-(4-(2-methylpyridin-4-yl)-2-(methylsulfonyl)phenoxy)pentan-2-amine(19 mg, 0.049 mmol, 83%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.51 (d, J=5.3 Hz,1H), 8.17-8.10 (m, 2H), 7.59 (s, 1H), 7.52-7.46 (m, 1H), 7.43 (d, J=9.2Hz, 1H), 3.97 (s, 2H), 3.55 (s, 3H), 2.55 (s, 3H), 1.83 (dt, J=13.0, 6.3Hz, 1H), 1.50-1.37 (m, 2H), 1.17 (s, 3H), 0.94 (dd, J=8.8, 6.5 Hz, 6H);LCMS (ESI) m/e 377.0 [(M+H)⁺, calcd C₂₀H₂₉N₂O₃S, 377.2]; LC/MS retentiontime (method B): t_(R)=1.32 min.

Example 115(S)-2,4-dimethyl-1-(2-(methylsulfonyl)-4-(quinolin-4-yl)phenoxy)pentan-2-amine

Prepared as described in Example 113 to afford(S)-2,4-dimethyl-1-(2-(methylsulfonyl)-4-(quinolin-4-yl)phenoxy)pentan-2-amine(12.2 mg, 0.029 mmol, 58%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.97 (d, J=4.4Hz, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.95-7.87 (m, 3H), 7.83 (t, J=7.7 Hz,1H), 7.65 (t, J=7.7 Hz, 1H), 7.55-7.47 (m, 2H), 4.01 (s, 2H), 3.49 (s,3H), 1.85 (dt, J=12.9, 6.5 Hz, 1H), 1.53-1.39 (m, 2H), 1.19 (s, 3H),0.97 (dd, J=8.4, 6.6 Hz, 6H); LCMS (ESI) m/e 413.0 [(M+H)⁺, calcdC₂₃H₂₉N₂O₃S, 413.2]; LC/MS retention time (method B): t_(R)=1.41 min.

Example 116(S)-1-(2-(difluoromethyl)-4-(6-fluoroquinolin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine

Part A:(S)-1-(2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2,4-dimethylpentan-2-amine

To a 5 mL vial was added(S)-1-(4-bromo-2-(difluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(16.2 mg, 0.048 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (14.68 mg,0.058 mmol), and potassium acetate (14.19 mg, 0.145 mmol) in dioxane(0.5 mL) to give a colorless suspension with nitrogen bubbling.PdCl₂(dppf) (1.058 mg, 1.446 μmol) was added under nitrogen. The vialwas sealed and the mixture was heated at 80° C. for 4 h. LCMS showedmost starting material was gone and several peaks. It was used directlyin the next step.

Part B:(S)-1-(2-(difluoromethyl)-4-(6-fluoroquinolin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine

The mixture of(S)-1-(2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2,4-dimethylpentan-2-amine(18.40 mg, 0.048 mmol),1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride,dichloromethane complex (2.74 mg, 3.36 μmol), Na₂CO₃ (0.096 mL, 0.192mmol) and 4-chloro-6-fluoroquinoline (8.72 mg, 0.048 mmol) in dioxane(0.5 mL) (degassed) (previous vial) was heated at 120° C. for 16 h. Thereaction mixture was diluted with ethyl acetate and dried (Na₂SO₄),filtered and concentrated. The residue was dissolved in MeOH andpurified by prep-HPLC to afford(S)-1-(2-(difluoromethyl)-4-(6-fluoroquinolin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine(6.7 mg, 35% for two steps): ¹H NMR (500 MHz, DMSO-d₆) δ 8.95 (d, J=4.5Hz, 1H), 8.20 (dd, J=9.2, 5.7 Hz, 1H), 7.74 (ddd, J=13.0, 8.0, 3.4 Hz,2H), 7.68 (d, J=2.3 Hz, 1H), 7.54 (d, J=4.4 Hz, 1H), 7.50 (dd, J=10.3,2.9 Hz, 1H), 7.44-7.17 (m, 2H), 3.61 (s, 2H), 1.82 (dq, J=12.8, 6.4 Hz,1H), 1.50-1.37 (m, 2H), 1.16 (s, 3H), 0.95 (dd, J=10.2, 6.6 Hz, 6H);LCMS (ESI) m/e 403.0 [(M+H)⁺, calcd C₂₃H₂₆F₃N₂O, 403.2]; LC/MS retentiontime (method B): t_(R)=1.78 min.

Example 117 (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate

Part A: 6-bromo-2-(difluoromethyl)-3-fluoropyridine

To a 100 mL round-bottomed flask was added6-bromo-3-fluoropicolinaldehyde (459.8 mg, 2.254 mmol) in CH₂Cl₂ (10 mL)to give a tan solution. After cooling to −20° C., DAST (0.596 mL, 4.51mmol) was added dropwise under nitrogen. The mixture was graduallywarmed up to rt. The mixture was stirred at rt for 3 h. TLC (3/1hexane/EtOAc) showed complete conversion to a less polar spot. Thereaction was slowly quenched by saturated NaHCO₃ solution and dilutedwith ether. The layers were separated. The organic layer was washed withwater, brine, dried and concentrated to6-bromo-2-(difluoromethyl)-3-fluoropyridine (509 mg, 100%) as a tansolid: ¹H NMR (400 MHz, Chloroform-d) δ 7.65 (ddt, J=8.6, 3.5, 1.0 Hz,1H), 7.46 (t, J=8.7 Hz, 1H), 6.73 (t, J=53.4 Hz, 1H); ¹⁹F NMR (376 MHz,Chloroform-d) δ −116.97, −127.89.

Part B:(S)-1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

To a 5 mL pressure bottle was added (S)-2-amino-2,4-dimethylpentan-1-ol(140 mg, 1.067 mmol) in tetrahydrofuran (1.3 mL) to give a colorlesssolution. Potassium tert-butoxide (1.280 mL, 1.280 mmol) (1.0 M in THF)was added dropwise under nitrogen. After 5 min,6-bromo-2-(difluoromethyl)-3-fluoropyridine (241 mg, 1.067 mmol) wasadded in one portion. The bottle was sealed and the mixture was stirredat 80° C. for 18 h. The mixture was partitioned between water and EtOAc.The layers were separated. The aqueous layer was extracted with EtOAc.The combined organic solution was washed with brine, dried andconcentrated to a tan oil (338 mg, 94%): ¹H NMR (400 MHz, Chloroform-d)δ 7.54 (dt, J=9.0, 1.1 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 6.74 (t, J=53.9Hz, 1H), 3.79 (d, J=1.7 Hz, 2H), 1.80 (dtd, J=13.3, 6.7, 1.1 Hz, 1H),1.54 (s, 2H), 1.52-1.47 (m, 2H), 1.25 (s, 3H), 1.00 (dd, J=8.3, 6.6 Hz,6H); ¹⁹F NMR (376 MHz, Chloroform-d) 6-117.98; LCMS (ESI) m/e 336.9[(M+H)⁺, calcd C₁₃H₂₀BrF₂N₂O, 337.1]; LC/MS retention time (method B):t_(R)=1.67 min.

Part C:(S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate

To a 2 mL vial was added(S)-1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(28.4 mg, 0.084 mmol), (2-((methoxycarbonyl)amino)pyridin-4-yl)boronicacid (41.3 mg, 0.211 mmol), and Na₂CO₃ (0.126 mL, 0.253 mmol) in dioxane(0.6 mL) to give a colorless suspension under nitrogen.1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, toluene(3.46 mg, 4.21 μmol) was added under nitrogen. The vial was sealed andheated at 100° C. (bath temp: 110° C.) for 3 h. The mixture was dilutedwith EtOAc and passed through a plug of Na₂SO₄. The organic solution wasconcentrated. The residue was purified twice by prep-HPLC to afford(S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate(12.6 mg, 37%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.50 (s, 1H), 8.36 (d, J=5.2Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.67 (dd,J=5.1, 1.7 Hz, 1H), 7.22 (t, J=53.6 Hz, 1H), 3.88 (s, 2H), 3.52 (s, 3H),1.86-1.73 (m, 1H), 1.47-1.33 (m, 2H), 1.13 (s, 3H), 0.93 (dd, J=10.0,6.6 Hz, 6H); LCMS (ESI) m/e 409.0 (M+H)⁺, calcd C₂₀H₂₇F₂N₄O₃, 409.2];LC/MS retention time (method B): t_(R)=1.66 min.

Example 118(S)-1-((2-(difluoromethyl)-6-(quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 117 to afford(S)-1-((2-(difluoromethyl)-6-(quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(10.6 mg, 0.027 mmol, 60% yield for three steps): ¹H NMR (500 MHz,DMSO-d₆) δ 9.01 (d, J=4.4 Hz, 1H), 8.21 (d, J=8.5 Hz, 1H), 8.13 (d,J=8.4 Hz, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.82 (t,J=7.7 Hz, 1H), 7.64 (dd, J=9.5, 6.0 Hz, 2H), 7.28 (t, J=53.6 Hz, 1H),3.53 (s, 2H), 1.83 (dt, J=13.2, 6.6 Hz, 1H), 1.50-1.37 (m, 2H), 1.16 (s,3H), 0.95 (dd, J=10.0, 6.7 Hz, 6H); LCMS (ESI) m/e 386.0 [(M+H)⁺, calcdC₂₂H₂₆F₂N₃O, 386.2]; LC/MS retention time (method B): t_(R)=1.54 min.

Example 119(S)-1-((6-(difluoromethyl)-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 117 to afford(S)-1-((6-(difluoromethyl)-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(18.3 mg, 0.051 mmol, 92% yield for three steps): ¹H NMR (500 MHz,DMSO-d₆) δ 8.54 (d, J=5.2 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 7.90 (s, 1H),7.82 (d, J=5.3 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.23 (t, J=53.6 Hz, 1H),3.89 (s, 2H), 2.56 (s, 3H), 1.81 (dq, J=12.8, 6.5 Hz, 1H), 1.50-1.34 (m,2H), 1.14 (s, 3H), 0.92 (dd, J=10.5, 6.6 Hz, 6H); LCMS (ESI) m/e 350.0[(M+H)⁺, calcd C₁₉H₂₆F₂N₃O, 350.2]; LC/MS retention time (method B):t_(R)=1.45 min.

Example 120 (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-(difluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate

Part A: 2-bromo-4-(difluoromethyl)-5-fluoropyridine

To a 100 mL round-bottomed flask was added2-bromo-5-fluoroisonicotinaldehyde (605 mg, 2.97 mmol) in CH₂Cl₂ (12 mL)to give a tan solution. After cooling to −20° C., DAST (0.705 mL, 5.34mmol) was added dropwise under nitrogen. The mixture was graduallywarmed up to rt. The mixture was stirred at rt for 3 h. TLC (3/1hexane/EtOAc) showed complete conversion to a less polar spot. Thereaction was slowly quenched by saturated NaHCO3 solution and dilutedwith ether. The layers were separated. The organic layer was washed withwater, brine, dried and concentrated to afford2-bromo-4-(difluoromethyl)-5-fluoropyridine (639 mg, 95%) as a tan oil:¹H NMR (400 MHz, Chloroform-d) δ 8.39 (q, J=1.2 Hz, 1H), 7.77-7.68 (m,1H), 6.86 (t, J=54.0 Hz, 1H); ¹⁹F NMR (376 MHz, Chloroform-d) δ −117.92,−135.51.

Part B:(S)-1-((6-bromo-4-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

To a 20 mL pressure bottle was added (S)-2-amino-2,4-dimethylpentan-1-ol(146 mg, 1.113 mmol) and 2-bromo-4-(difluoromethyl)-5-fluoropyridine(251 mg, 1.113 mmol) in tetrahydrofuran (1.5 mL) to give a tan solution.Potassium tert-butoxide (1.335 mL, 1.335 mmol) (1.0 M in THF) was addeddropwise under nitrogen. After 5 min stirring at rt, the bottle wassealed and the mixture was stirred at 80° C. for 18 h. The mixture waspartitioned between water and EtOAc. The layers were separated. Theaqueous layer was extracted with EtOAc. The combined organic solutionwas washed with brine, dried and concentrated to a tan oil (361 mg,96%): ¹H NMR (400 MHz, Chloroform-d) δ 8.13 (s, 1H), 7.62 (s, 1H), 6.85(t, J=54.4 Hz, 1H), 3.87 (s, 2H), 1.80 (dtd, J=13.2, 6.7, 1.0 Hz, 1H),1.61-1.50 (m, 2H), 1.50-1.47 (m, 2H), 1.24 (s, 3H), 1.00 (dd, J=7.4, 6.7Hz, 6H); ¹⁹F NMR (376 MHz, Chloroform-d) δ −119.58; LCMS (ESI) m/e 336.9[(M+H)⁺, calcd C₁₃H₂₀BrF₂N₂O, 337.1]; LC/MS retention time (method B):t_(R)=1.79 min.

Part C: (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-(difluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate

Prepared as described in Example 117 to afford (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-(difluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate(2.5 mg, 0.006 mmol, 6% yield for three steps): ¹H NMR (500 MHz,DMSO-d₆) δ 8.71 (s, 1H), 8.53 (s, 1H), 8.36 (d, J=5.2 Hz, 1H), 8.08 (s,1H), 7.71 (d, J=5.2 Hz, 1H), 7.48 (t, J=53.9 Hz, 1H), 4.12 (s, 2H), 3.71(s, 3H), 1.82 (dt, J=12.9, 6.4 Hz, 1H), 1.53 (dd, J=14.2, 5.3 Hz, 1H),1.46 (dd, J=14.2, 5.8 Hz, 1H), 1.22 (s, 3H), 0.95 (d, J=6.6 Hz, 3H),0.91 (d, J=6.6 Hz, 3H); LCMS (ESI) m/e 408.9 (M+H)⁺, calcd C₂₀H₂₇F₂N₄O₃,409.2]; LC/MS retention time (method B): t_(R)=1.66 min.

Example 121(S)-1-((4-(difluoromethyl)-6-(quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 117 to afford(S)-1-((4-(difluoromethyl)-6-(quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(11.7 mg, 0.030 mmol, 69% yield for three steps): ¹H NMR (500 MHz,DMSO-d₆) δ 9.00 (d, J=4.4 Hz, 1H), 8.78 (s, 1H), 8.18 (d, J=8.5 Hz, 1H),8.13 (d, J=8.5 Hz, 1H), 7.88 (s, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.69-7.60(m, 2H), 7.39 (t, J=53.8 Hz, 1H), 4.06 (s, 2H), 1.84 (dt, J=12.9, 6.3Hz, 1H), 1.51-1.37 (m, 2H), 1.17 (s, 3H), 0.96 (dd, J=11.7, 6.7 Hz, 6H);LCMS (ESI) m/e 386.0 [(M+H)⁺, calcd C₂₂H₂₆F₂N₃O, 386.2]; LC/MS retentiontime (method B): t_(R)=1.58 min.

Example 122(S)-1-((4-(difluoromethyl)-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 117 to afford(S)-1-((4-(difluoromethyl)-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(13.6 mg, 0.039 mmol, 74% yield for three steps): ¹H NMR (500 MHz,DMSO-d₆) δ 8.68 (s, 1H), 8.54 (d, J=5.3 Hz, 1H), 8.19 (s, 1H), 7.94 (s,1H), 7.84 (d, J=5.2 Hz, 1H), 7.39 (t, J=53.9 Hz, 1H), 4.06 (s, 2H), 2.56(s, 3H), 1.81 (dt, J=12.8, 6.4 Hz, 1H), 1.45 (qd, J=14.2, 5.7 Hz, 2H),1.18 (s, 3H), 0.94 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H); LCMS (ESI)m/e 350.0 [(M+H)⁺, calcd C₁₉H₂₆F₂N₃O, 350.2]; LC/MS retention time(method B): t_(R)=1.46 min.

Example 123(S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (2-(difluoromethyl)pyridin-4-yl)boronic acid

To a 20 mL vial was added 4-chloro-2-(difluoromethyl)pyridinehydrochloride (180 mg, 0.900 mmol), hypodiboric acid (121 mg, 1.350mmol), 2-(dicyclohexylphosphino))-2′,4′,6′-triisopropylbiphenyl (8.58mg, 0.018 mmol), Xphos precatalyst (7.08 mg, 9.00 μmol) and potassiumacetate (265 mg, 2.70 mmol) in ethanol (8.5 mL) to give a tan suspension(degassed before adding agents). The bottle was capped and heated at 80°C. for 1.5 h. LCMS showed the consumption of the starting material andformation of a new spot: (2-(difluoromethyl)pyridin-4-yl)boronic acid.The mixture was divided into parts and directly used in the next step ofdifferent reactions.

Part B:(S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

To a 5 mL vial was added (2-(difluoromethyl)pyridin-4-yl)boronic acid(25.9 mg, 0.15 mmol) was added potassium phosphate tribasic (1 mL, 0.500mmol). After degassing for 5 min, Xphos precatalyst (4 mg, 5.08 μmol)and(S)-1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(26.5 mg, 0.079 mmol) and tetrahydrofuran (1 mL) were added. The vialwas sealed and heated at 80° C. overnight for 18 h. Volatiles were blownoff. The residue was partitioned between EtOAc and water. The organiclayer was dried, filtered and concentrated. The residue was dissolved inMeOH and purified by prep-HPLC to afford(S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(29.8 mg, 98%) as a colorless solid. ¹H NMR (500 MHz, DMSO-d6) δ 8.79(d, J=5.2 Hz, 1H), 8.40 (d, J=8.8 Hz, 1H), 8.32 (s, 1H), 8.21 (d, J=5.1Hz, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.31 (t, J=53.5 Hz, 1H), 7.04 (t,J=54.9 Hz, 1H), 3.96 (s, 2H), 3.46 (s, 2H), 1.80 (dp, J=12.5, 6.7, 6.3Hz, 1H), 1.45 (qd, J=14.1, 5.6 Hz, 2H), 1.17 (s, 3H), 0.92 (dd, J=13.6,6.6 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −115.43 (d, J=55.2 Hz),−117.78-−119.55 (m); LCMS (ESI) m/e 386.0 [(M+H)⁺, calcd C₁₉H₂₄F₄N₃O,386.2]; LC/MS retention time (method B): t_(R)=1.85 min.

Example 124(S)-1-((2′,4-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 123 to afford(S)-1-((2′,4-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(25.9 mg, 0.067 mmol, 77% yield) as a colorless solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.79 (d, J=5.2 Hz, 1H), 8.71 (s, 1H), 8.36 (s, 1H), 8.32 (s,1H), 8.25 (d, J=5.1 Hz, 1H), 7.35 (t, J=53.9 Hz, 1H), 7.04 (t, J=54.9Hz, 1H), 4.03 (s, 2H), 1.81 (dt, J=12.8, 6.4 Hz, 1H), 1.48-1.33 (m, 2H),1.14 (s, 3H), 0.93 (dd, J=12.3, 6.6 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆)δ −115.44 (d, J=54.7 Hz), −116.34-−119.67 (m); LCMS (ESI) m/e 386.0[(M+H)⁺, calcd C₁₉H₂₄F₄N₃O, 386.2]; LC/MS retention time (method B):t_(R)=1.83 min.

Example 125(S)-1-((2′-(difluoromethyl)-4-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((2′-(difluoromethyl)-4-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Prepared as described in Example 123 to afford (S)-tert-butyl(1-((2′-(difluoromethyl)-4-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(38.5 mg, 0.086 mmol, 80% yield) as a colorless solid. ¹H NMR (400 MHz,Chloroform-d) δ 8.71 (d, J=5.2 Hz, 1H), 8.31 (s, 1H), 8.18 (d, J=1.7 Hz,1H), 7.98 (dd, J=5.2, 1.7 Hz, 1H), 7.66 (s, 1H), 6.72 (t, J=55.5 Hz,1H), 4.63 (s, 1H), 4.32 (d, J=8.7 Hz, 1H), 4.14 (d, J=8.8 Hz, 1H), 2.36(s, 3H), 1.96-1.77 (m, 2H), 1.65-1.54 (m, 1H), 1.44 (s, 3H), 1.42 (s,9H), 1.01 (dd, J=6.6, 3.5 Hz, 6H); ¹⁹F NMR (376 MHz, Chloroform-d) δ−115.81; LCMS (ESI) m/e 450.1 [(M+H)⁺, calcd C₂₄H₃₄F₂N₃O₃, 450.2]; LC/MSretention time (method B): t_(R)=2.31 min.

Part B:(S)-1-((2′-(difluoromethyl)-4-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 7, Part B (34.9 mg, 100%):¹H NMR (500 MHz, DMSO-d₆) δ 8.76 (d, J=5.1 Hz, 1H), 8.42 (s, 1H), 8.31(s, 1H), 8.22-8.15 (m, 1H), 8.12 (s, 1H), 7.03 (t, J=55.0 Hz, 1H),4.13-4.00 (m, 2H), 2.36 (s, 3H), 1.83 (dp, J=12.7, 6.5 Hz, 1H), 1.60(dd, J=14.1, 5.5 Hz, 1H), 1.52 (dd, J=14.1, 5.6 Hz, 1H), 1.27 (s, 3H),0.95 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H); ¹⁹F NMR (376 MHz,DMSO-d6) δ −115.37 (d, J=54.8 Hz); LCMS (ESI) m/e 350.0 [(M+H)⁺, calcdC₁₉H₂₆F₂N₃O, 350.2]; LC/MS retention time (method B): t_(R)=1.80 min.

Example 126(S)-1-(2-cyclopropyl-4-(2-(difluoromethyl)pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-(2-cyclopropyl-4-(2-(difluoromethyl)pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate

Prepared as described in Example 123 to afford (S)-tert-butyl(1-(2-cyclopropyl-4-(2-(difluoromethyl)pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate(31.4 mg, 0.066 mmol, 79% yield) as a colorless solid. ¹H NMR (400 MHz,Chloroform-d) δ 8.65 (d, J=5.1 Hz, 1H), 7.79 (d, J=1.7 Hz, 1H), 7.56(dd, J=5.2, 1.8 Hz, 1H), 7.47 (dd, J=8.4, 2.4 Hz, 1H), 7.23 (d, J=2.3Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.71 (t, J=55.5 Hz, 1H), 4.73 (s, 1H),4.21 (d, J=8.8 Hz, 1H), 4.05 (d, J=8.8 Hz, 1H), 2.19 (tt, J=8.6, 5.4 Hz,1H), 1.87 (ddt, J=13.1, 11.4, 6.8 Hz, 2H), 1.72-1.62 (m, 1H), 1.47 (s,3H), 1.43 (s, 9H), 1.01 (dt, J=5.5, 2.7 Hz, 8H), 0.74 (td, J=5.7, 4.0Hz, 2H); ¹⁹F NMR (376 MHz, Chloroform-d) δ −115.77; LCMS (ESI) m/e 475.0[(M+H)⁺, calcd C₂₇H₃₇F₂N₂O₃, 475.3]; LC/MS retention time (method B):t_(R)=2.48 min.

Part B:(S)-1-(2-cyclopropyl-4-(2-(difluoromethyl)pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 7, Part B (25.8 mg, 100%) asa colorless solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.66 (d, J=5.3 Hz, 1H),7.94 (s, 1H), 7.86 (d, J=5.3 Hz, 1H), 7.66 (dd, J=8.6, 2.3 Hz, 1H), 7.32(d, J=2.4 Hz, 1H), 7.11-6.84 (m, 2H), 3.90-3.79 (m, 2H), 2.26 (td,J=8.5, 4.2 Hz, 1H), 1.82 (hept, J=6.4 Hz, 1H), 1.50 (qd, J=14.1, 5.6 Hz,2H), 1.21 (s, 3H), 0.98-0.88 (m, 8H), 0.86-0.73 (m, 2H); ¹⁹F NMR (376MHz, DMSO-d6) δ −115.05 (d, J=54.9 Hz); LCMS (ESI) m/e 375.0 [(M+H)⁺,calcd C₂₂H₂₉F₂N₂O, 375.2]; LC/MS retention time (method B): t_(R)=1.97min.

Example 127(S)-1-((2-(difluoromethyl)-6-(6-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Part A:(S)-1-((2-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

To a 5 mL vial was added(S)-1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(79.5 mg, 0.236 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (71.8 mg,0.283 mmol), and potassium acetate (69.4 mg, 0.707 mmol) in dioxane (2.4mL) to give a colorless suspension with nitrogen bubbling. PdCl₂(dppf)(5.18 mg, 7.07 μmol) was added under nitrogen. The vial was sealed andthe mixture was heated at 80° C. for 20 h. LC/MS showed completeconversion to a new peak. It was divided into parts and used directly inthe next step. LC/MS retention time (method B): t_(R)=1.52 min.

Part B:(S)-1-((2-(difluoromethyl)-6-(6-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 116 to afford(S)-1-((2-(difluoromethyl)-6-(6-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(5.3 mg, 16% for 2 steps) as a colorless solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.97 (d, J=4.5 Hz, 1H), 8.19 (dd, J=9.3, 5.5 Hz, 1H),7.85 (dd, J=10.4, 2.9 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.59-7.43 (m,3H), 7.09-6.72 (t, J=54.0 Hz, 1H), 4.01-3.84 (m, 2H), 1.91-1.78 (m, 1H),1.61-1.49 (m, 2H), 1.31 (s, 3H), 1.03 (app t, J=7.0 Hz, 6H), twoexchangeable protons not observed; LCMS (ESI) m/e 404.0 [(M+H)⁺, calcdC₂₂H₂₅F₃N₃O, 404.2]; LC/MS retention time (method B): t_(R)=1.81 min.

Example 128(S)-1-((2-(difluoromethyl)-6-(7-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 116 to afford(S)-1-((2-(difluoromethyl)-6-(7-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(11.1 mg, 35% for 2 steps) as a colorless solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.98 (d, J=4.5 Hz, 1H), 8.21 (dd, J=9.3, 6.0 Hz, 1H),7.81 (dd, J=9.9, 2.6 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.50 (d, J=8.8 Hz,1H), 7.45 (d, J=4.5 Hz, 1H), 7.35 (ddd, J=9.3, 8.0, 2.8 Hz, 1H), 6.98(t, J=55.0 Hz, 1H), 3.98 (s, 2H), 1.85 (tt, J=12.7, 6.4 Hz, 1H),1.68-1.56 (m, 2H), 1.36 (s, 3H), 1.03 (d, J=6.8 Hz, 3H), 1.01 (d, J=6.8Hz, 3H), two exchangeable protons not observed; LCMS (ESI) m/e 404.0[(M+H)⁺, calcd C₂₂H₂₅F₃N₃O, 404.2]; LC/MS retention time (method B):t_(R)=1.68 min.

Example 129(S)-1-((2-(difluoromethyl)-6-(5,7-difluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 16 to afford(S)-1-((2-(difluoromethyl)-6-(5,7-difluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(25.9 mg, 75% for 2 steps) as a colorless solid. ¹H NMR (600 MHz,DMSO-d₆) δ 9.13-9.02 (m, 1H), 7.93-7.73 (m, 3H), 7.56 (dt, J=23.8, 6.1Hz, 2H), 7.38-7.09 (m, 1H), 3.95 (d, J=22.2 Hz, 2H), 1.84 (dt, J=18.4,6.3 Hz, 1H), 1.45 (dtd, J=23.9, 14.0, 11.7, 5.4 Hz, 2H), 1.27-1.14 (m,3H), 0.96 (ddd, J=23.9, 13.5, 6.6 Hz, 6H); LCMS (ESI) m/e 421.9 [(M+H)⁺,calcd C₂₂H₂₄F₄N₃O, 422.2]; LC/MS retention time (method B): t_(R)=1.82min.

Example 130(S)-1-((4-(difluoromethyl)-6-(5,7-difluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Part A:5,7-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Prepared as previously described in Example 127. Obtained5,7-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolinewhich was divided into parts and used directly in the next step. LC/MSretention time (method A): t_(R)=1.93 min.

Part B:(S)-1-((4-(difluoromethyl)-6-(5,7-difluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 16 to afford(S)-1-((4-(difluoromethyl)-6-(5,7-difluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(14.7 mg, 49% for 2 steps) as a colorless solid. ¹H NMR (600 MHz,DMSO-d₆) δ 9.04 (d, J=4.7 Hz, 1H), 8.62 (d, J=5.7 Hz, 1H), 7.80 (d,J=9.6 Hz, 1H), 7.75 (d, J=6.5 Hz, 1H), 7.56 (qd, J=8.5, 7.9, 4.9 Hz,2H), 7.36 (t, J=53.9 Hz, 1H), 4.01 (s, 2H), 1.82 (q, J=6.5 Hz, 1H), 1.43(qd, J=14.0, 5.9 Hz, 2H), 1.16 (s, 3H), 0.94 (dd, J=14.6, 6.7 Hz, 6H);¹⁹F NMR (376 MHz, DMSO-d₆)δ −102.43 (d, J=9.6 Hz), −107.91 (d, J=9.0Hz), −116.03-−119.87 (m); LCMS (ESI) m/e 422.0 [(M+H)⁺, calcdC₂₂H₂₄F₄N₃O, 422.2]; LC/MS retention time (method B): t_(R)=1.88 min.

Example 131(S)-1-((4-(difluoromethyl)-6-(7-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Part A:7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Prepared as previously described in Example 127. Obtained7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline whichwas divided into parts and used directly in the next step. LC/MSretention time (method A): t_(R)=1.19 min.

Part B:(S)-1-((4-(difluoromethyl)-6-(7-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 16 to afford(S)-1-((4-(difluoromethyl)-6-(7-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(11.1 mg, 39% for 2 steps) as a colorless solid. ¹H NMR (600 MHz,DMSO-d₆) δ 9.02 (d, J=4.3 Hz, 1H), 8.77 (s, 1H), 8.30 (ddd, J=9.0, 6.3,2.4 Hz, 1H), 7.90 (s, 1H), 7.86 (dd, J=10.2, 2.7 Hz, 1H), 7.67 (d, J=4.3Hz, 1H), 7.58 (td, J=8.8, 2.7 Hz, 1H), 7.37 (t, J=53.9 Hz, 1H), 4.05 (s,2H), 1.83 (p, J=6.5 Hz, 1H), 1.43 (qd, J=14.0, 5.4 Hz, 2H), 1.16 (s,3H), 0.95 (ddd, J=13.9, 6.8, 2.1 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−110.25, −115.90-−119.14 (m); LCMS (ESI) m/e 404.0 [(M+H)⁺, calcdC₂₂H₂₅F₃N₃O, 404.2]; LC/MS retention time (method B): t_(R)=1.78 min.

Example 132(S)-1-((4-(difluoromethyl)-6-(6-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Part A:(S)-1-((4-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

To a 5 mL vial was added(S)-1-((6-bromo-4-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(82.5 mg, 0.245 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (74.6 mg,0.294 mmol), and potassium acetate (72.0 mg, 0.734 mmol) in dioxane (2.4mL) to give a colorless suspension with nitrogen bubbling. PdCl₂(dppf)(5.37 mg, 7.34 μmol) was added under nitrogen. The vial was sealed andthe mixture was heated at 80° C. for 20 h. LCMS showed mainly thestarting material (dark red color mixture). The temperature was raisedto 100° C. After 4 h, LCMS showed a little better conversion. Thereaction continued for another 16 h at 100° C. LCMS showed betterconversion but there was still some starting material left. Thetemperature was raised to 110° C. and the reaction continued for 5 h.LCMS showed only a little starting material left. The reaction continuedat 110° C. for another 5 h. After cooling down, the reaction mixture wasdivided into parts and used directly in the next step.

Part B:(S)-1-((4-(difluoromethyl)-6-(6-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 116 to afford(S)-1-((4-(difluoromethyl)-6-(6-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(1.6 mg, 5% for 2 steps) as a colorless solid. ¹H NMR (600 MHz, DMSO-d₆)δ 8.99 (d, J=4.4 Hz, 1H), 8.80 (s, 1H), 8.20 (dd, J=9.3, 5.6 Hz, 1H),8.01 (dd, J=11.0, 2.9 Hz, 1H), 7.94 (s, 1H), 7.79-7.70 (m, 2H), 7.40 (t,J=53.9 Hz, 1H), 4.09 (s, 2H), 1.84 (dt, J=12.8, 6.5 Hz, 1H), 1.46 (qd,J=14.0, 5.6 Hz, 2H), 1.19 (s, 3H), 0.97 (d, J=6.6 Hz, 3H), 0.94 (d,J=6.6 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −112.45, −118.42 (dd,J=134.0, 57.0 Hz); LCMS (ESI) m/e 404.0 [(M+H)⁺, calcd C₂₂H₂₅F₃N₃O,404.2]; LC/MS retention time (method B): t_(R)=1.79 min.

Example 133((S)-1-((4-(difluoromethyl)-6-(6-(trifluoromethyl)quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 132 to afford((S)-1-((4-(difluoromethyl)-6-(6-(trifluoromethyl)quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(2.1 mg, 6% for 2 steps) as a colorless solid. ¹H NMR (600 MHz, DMSO-d₆)δ 9.17 (d, J=4.4 Hz, 1H), 8.85 (s, 1H), 8.75 (s, 1H), 8.34 (d, J=8.8 Hz,1H), 8.08 (dd, J=8.8, 2.1 Hz, 1H), 8.02 (s, 1H), 7.88 (d, J=4.3 Hz, 1H),7.43 (t, J=53.9 Hz, 1H), 4.13 (d, J=3.0 Hz, 2H), 1.84 (p, J=6.2 Hz, 1H),1.57-1.41 (m, 2H), 1.21 (s, 3H), 0.97 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.5Hz, 3H); LCMS (ESI) m/e 454.0 [(M+H)⁺, calcd C₂₃H₂₅F₅N₃O, 454.2]; LC/MSretention time (method B): t_(R)=2.02 min.

Example 134(S)-1-((4-(difluoromethyl)-6-(6-(trifluoromethoxy)quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 132 to afford(S)-1-((4-(difluoromethyl)-6-(6-(trifluoromethoxy)quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(1.5 mg, 4% for 2 steps) as a colorless solid. ¹H NMR (600 MHz, DMSO-d₆)δ 9.07 (d, J=4.4 Hz, 1H), 8.80 (s, 1H), 8.29 (s, 1H), 8.27 (d, J=9.2 Hz,1H), 7.97 (s, 1H), 7.83 (dd, J=8.7, 3.2 Hz, 2H), 7.38 (t, J=53.9 Hz,1H), 4.06 (s, 2H), 1.84 (dt, J=12.7, 6.3 Hz, 1H), 1.42 (qd, J=14.0, 5.6Hz, 2H), 1.16 (s, 3H), 0.96 (d, J=6.5 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H);LCMS (ESI) m/e 470.0 [(M+H)⁺, calcd C₂₃H₂₅F₅N₃O₂, 470.2]; LC/MSretention time (method B): t_(R)=2.00 min.

Example 135(S)-1-((2-chloro-6-(5,7-difluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((2-chloro-6-(5,7-difluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Prepared as previously described in Example 66. The intermediates wereas described in Example 66 and Example 130 to afford (S)-tert-butyl(1-((2-chloro-6-(5,7-difluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(12.1 mg, 34%) as a colorless solid. ¹H NMR (400 MHz, Chloroform-d) δ8.97 (d, J=4.4 Hz, 1H), 7.68 (ddd, J=9.5, 2.6, 1.5 Hz, 1H), 7.42-7.32(m, 3H), 7.05 (ddd, J=11.5, 8.8, 2.6 Hz, 1H), 4.64 (s, 1H), 4.37 (d,J=8.9 Hz, 1H), 4.18 (d, J=8.9 Hz, 1H), 1.96 (dd, J=13.9, 6.4 Hz, 1H),1.87 (ddd, J=13.1, 6.5, 4.9 Hz, 1H), 1.58 (dd, J=13.9, 4.9 Hz, 1H), 1.47(s, 3H), 1.42 (s, 9H), 1.04 (s, 3H), 1.02 (s, 3H); ¹⁹F NMR (376 MHz,Chloroform-d) δ −102.47, −107.56; LCMS (ESI) m/e 506.0 [(M+H)⁺, calcdC₂₆H₃₁ClF₂N₃O₃, 506.2]; LC/MS retention time (method B): t_(R)=2.36 min.

Part B:(S)-1-((2-chloro-6-(5,7-difluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 7, Part B to afford(S)-1-((2-chloro-6-(5,7-difluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(10.6 mg, 100%) as a colorless solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ8.97 (d, J=4.3 Hz, 1H), 7.77-7.62 (m, 1H), 7.40 (d, J=4.3 Hz, 1H),7.38-7.34 (m, 1H), 7.33-7.28 (m, 1H), 7.05 (ddd, J=11.6, 8.8, 2.6 Hz,1H), 3.93-3.84 (m, 2H), 1.92-1.73 (m, 1H), 1.66-1.50 (m, 2H), 1.32 (s,3H), 1.04 (d, J=6.8 Hz, 3H), 1.02 (d, J=6.5 Hz, 3H), two exchangeableprotons not observed; ¹⁹F NMR (376 MHz, DMSO-d6) δ −101.38-−103.03 (m),−105.03-−107.99 (m); LCMS (ESI) m/e 405.9 [(M+H)⁺, calcd C₂₁H₂₃ClF₂N₃O,406.1]; LC/MS retention time (method B): t_(R)=1.84 min.

Example 136(S)-1-((2-chloro-6-(7-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((2-chloro-6-(7-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Prepared as previously described in Example 66. The intermediates wereas described in Example 66 and Example 131 to afford (S)-tert-butyl(1-((2-chloro-6-(7-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(12.4 mg, 36%) as a colorless solid. ¹H NMR (400 MHz, Chloroform-d) δ8.98 (d, J=4.5 Hz, 1H), 8.24 (dd, J=9.4, 6.1 Hz, 1H), 7.81 (dd, J=9.9,2.6 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.49-7.43 (m, 2H), 7.37 (ddd,J=9.3, 8.0, 2.7 Hz, 1H), 4.64 (s, 1H), 4.41 (d, J=9.0 Hz, 1H), 4.21 (d,J=9.0 Hz, 1H), 2.01-1.82 (m, 2H), 1.58 (dd, J=13.9, 5.0 Hz, 1H), 1.48(s, 3H), 1.42 (s, 9H), 1.05 (s, 3H), 1.03 (s, 3H); ¹⁹F NMR (376 MHz,Chloroform-d) δ −109.85; LCMS (ESI) m/e 488.0 [(M+H)⁺, calcdC₂₆H₃₂ClFN₃O₃, 488.2]; LC/MS retention time (method B): t_(R)=2.28 min.

Part B:(S)-1-((2-chloro-6-(7-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 7, Part B to afford(S)-1-((2-chloro-6-(7-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(11.1 mg, 100%) as a colorless solid. ¹H NMR (600 MHz, DMSO-d₆) δ 9.01(d, J=4.4 Hz, 1H), 8.32 (dd, J=9.4, 6.1 Hz, 1H), 7.88-7.77 (m, 3H), 7.63(d, J=4.2 Hz, 1H), 7.60 (td, J=8.8, 2.7 Hz, 1H), 3.98-3.89 (m, 2H), 1.85(dq, J=12.8, 6.4 Hz, 1H), 1.50-1.40 (m, 2H), 1.18 (s, 3H), 0.95 (dd,J=7.5, 5.4 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ −110.18; LCMS (ESI) m/e388.0 [(M+H)⁺, calcd C₂₁H₂₄ClFN₃O, 388.2]; LC/MS retention time (methodB): t_(R)=1.76 min.

Example 137(S)-1-((6-(7-fluoroquinolin-4-yl)-2-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Part A:(S)-1-((6-bromo-2-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

To a 20 mL pressure bottle was added (S)-2-amino-2,4-dimethylpentan-1-ol(214.8 mg, 1.637 mmol) in tetrahydrofuran (2.2 mL) to give a colorlesssolution. Potassium tert-butoxide (2.128 mL, 2.128 mmol) (1.0 M in THF)was added dropwise under nitrogen. After 5 min,6-bromo-3-fluoro-2-methylpyridine (311 mg, 1.637 mmol) was added in oneportion. The bottle was sealed and the mixture was stirred at 80° C. for20 h. The mixture was partitioned between water and EtOAc. The layerswere separated. The aqueous layer was extracted with EtOAc. The combinedorganic solution was washed with brine, dried and concentrated to a tanoil. It was purified by silica gel chromatography up to 10% MeOH (2NNH₃) in CH₂Cl₂ to afford(S)-1-((6-bromo-2-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(220 mg, 45% with one unknown impurity-likely substitution at Br). LCMS(ESI) m/e 283.9 [(M-NH₂)+, calcd C₁₃H₁₉BrNO, 284.1]; LC/MS retentiontime (method B): t_(R)=1.70 min (impurity: 1.81 min).

Part B:(S)-2,4-dimethyl-1-((2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)oxy)pentan-2-amine

To a 5 mL vial was added(S)-1-((6-bromo-2-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(89.5 mg, 0.267 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (81 mg,0.321 mmol), and potassium acetate (79 mg, 0.802 mmol) in dioxane (2.8mL) to give a colorless suspension with nitrogen bubbling. PdCl₂(dppf)(5.87 mg, 8.02 μmol) was added under nitrogen. The vial was sealed andthe mixture was heated at 80° C. for 18 h. LCMS showed there wassubstantial amount of starting material. The reaction mixture was heatedat 100° C. for 4 h. LCMS showed the majority of starting material wasgone (the side product from previous reaction remained). It was dividedinto parts and used directly in the next step.

Part C:(S)-1-((6-(7-fluoroquinolin-4-yl)-2-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 132 to afford(S)-1-((6-(7-fluoroquinolin-4-yl)-2-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(1.0 mg, 3%) as a colorless solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.99 (d,J=4.5 Hz, 1H), 8.37 (dd, J=9.3, 6.4 Hz, 1H), 7.84 (dd, J=10.4, 2.7 Hz,1H), 7.65 (d, J=8.4 Hz, 1H), 7.62-7.54 (m, 3H), 3.98 (s, 2H), 2.57 (s,3H), 1.90-1.80 (m, 1H), 1.61 (d, J=5.3 Hz, 1H), 1.53 (dd, J=14.0, 5.5Hz, 1H), 1.30 (s, 3H), 0.98 (d, J=6.6 Hz, 3H), 0.96 (d, J=6.7 Hz, 3H).LCMS (ESI) m/e 368.2 [(M+H)⁺, calcd C₂₂H₂₇FN₃O, 368.2].

Example 138(S)-1-((6-(6-fluoroquinolin-4-yl)-2-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 132 with intermediate fromExample 137 to afford(S)-1-((6-(6-fluoroquinolin-4-yl)-2-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(1.5 mg, 3%, 64% purity by analytical HPLC): ¹H NMR (500 MHz, DMSO-d₆) δ8.96 (d, J=4.4 Hz, 1H), 8.17 (dd, J=9.4, 5.7 Hz, 1H), 8.07 (dd, J=10.8,2.8 Hz, 1H), 7.78-7.51 (m, 5H), 6.70 (dd, J=8.8, 2.6 Hz, 1H), 3.93-3.77(m, 2H), 2.55 (s, 3H), 1.87-1.72 (m, 1H), 1.58-1.30 (m, 2H), 1.15 (s,3H), 1.00-0.83 (m, 6H) LCMS (ESI) m/e 368.2 [(M+H)⁺, calcd C₂₂H₂₇FN₃O,368.2].

Example 139(S)-1-((2-(difluoromethyl)-6-(2-methylpyrimidin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 127 with intermediate asdescribed in Example 127 and 4-bromo-2-methylpyrimidine to afford(S)-1-((2-(difluoromethyl)-6-(2-methylpyrimidin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(15.9 mg, 45%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.82 (d, J=5.2 Hz, 1H), 8.57(d, J=8.9 Hz, 1H), 8.07 (d, J=5.3 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.26(t, J=53.6 Hz, 1H), 3.92 (s, 2H), 2.71 (s, 3H), 1.81 (dd, J=12.9, 6.6Hz, 1H), 1.47-1.36 (m, 2H), 1.15 (s, 3H), 0.93 (dd, J=11.0, 6.8 Hz, 6H);LCMS (ESI) m/e 373.1 [(M+Na)⁺, calcd C₁₈H₂₄F₂N₄NaO, 373.2]; LC/MSretention time (method B): t_(R)=1.73 min.

Example 140(S)-1-((2-(difluoromethyl)-6-(6-methylpyrimidin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 127 with intermediate asdescribed in Example 127 and 4-bromo-6-methylpyrimidine to afford(S)-1-((2-(difluoromethyl)-6-(6-methylpyrimidin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(3.5 mg, 6.8%): ¹H NMR (400 MHz, CHLOROFORM-d) δ 9.11 (d, J=1.3 Hz, 1H),8.58 (d, J=8.8 Hz, 1H), 8.21 (s, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.10-6.72(t, J=53.0 Hz, 1H), 3.96 (s, 2H), 2.63 (s, 3H), 1.88-1.75 (m, 1H),1.66-1.52 (m, 2H), 1.26 (s, 3H), 1.01 (d, J=6.5 Hz, 3H), 0.98 (d, J=6.8Hz, 3H), two exchangeable protons not observed; LCMS (ESI) m/e 334.1[(M-NH₂)+, calcd C₁₈H₂₂F₂N₃O, 334.2]; LC/MS retention time (method B):t_(R)=1.78 min.

Example 141(S)-1-((4-(difluoromethyl)-2′-ethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 117 with intermediate asdescribed in Example 120 and (2-ethylpyridin-4-yl)boronic acid to afford(S)-1-((4-(difluoromethyl)-2′-ethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(8.0 mg, 39%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.57 (d, J=5.2Hz, 1H), 8.20 (s, 1H), 7.93 (s, 1H), 7.85 (dd, J=5.2, 1.6 Hz, 1H), 7.34(t, J=53.9 Hz, 1H), 4.01 (s, 2H), 2.84 (q, J=7.6 Hz, 2H), 1.80 (dq,J=12.5, 6.2 Hz, 1H), 1.47-1.35 (m, 2H), 1.28 (t, J=7.6 Hz, 3H), 1.14 (s,3H), 0.93 (dd, J=12.6, 6.6 Hz, 6H); LCMS (ESI) m/e 364.2 [(M+H)⁺, calcdC₂H₂₈F₂N₃O, 364.2]; LC/MS retention time (method B): t_(R)=1.54 min.

Example 142(S)-1-((2′-chloro-4-(difluoromethyl)-3′-fluoro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 117 with intermediate asdescribed in Example 120 and (2-chloro-3-fluoro-pyridin-4-yl)boronicacid to afford(5)-1-((2′-chloro-4-(difluoromethyl)-3′-fluoro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(10.8 mg, 13%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.38 (d, J=5.0Hz, 1H), 8.05 (s, 1H), 7.97 (t, J=5.3 Hz, 1H), 7.37 (t, J=53.9 Hz, 1H),4.03 (s, 2H), 1.81 (dt, J=12.8, 6.4 Hz, 1H), 1.45-1.35 (m, 2H), 1.14 (s,3H), 0.93 (dd, J=12.4, 6.7 Hz, 7H); LCMS (ESI) m/e 371.1 [(M-NH₂)+,calcd C₁₈H₁₉ClF₃N₂O, 371.1]; LC/MS retention time (method B): t_(R)=1.98min.

Example 143(S)-1-((2′-chloro-4-(difluoromethyl)-5′-fluoro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 117 with intermediate asdescribed in Example 120 and (2-chloro-5-fluoro-pyridin-4-yl)boronicacid to afford(S)-1-((2′-chloro-4-(difluoromethyl)-5′-fluoro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(9.6 mg, 11%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.61 (d, J=2.6Hz, 1H), 8.05 (s, 1H), 8.02 (d, J=5.5 Hz, 1H), 7.37 (t, J=53.9 Hz, 1H),4.04 (s, 2H), 1.81 (dt, J=12.6, 6.4 Hz, 1H), 1.46-1.35 (m, 2H), 1.14 (s,3H), 0.93 (dd, J=12.8, 6.6 Hz, 6H); LCMS (ESI) m/e 371.1 [(M-NH₂)+,calcd C₁₈H₁₉ClF₃N₂O, 371.1]; LC/MS retention time (method B): t_(R)=1.97min.

Example 144(S)-2,4-dimethyl-1-((2′-methyl-4-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)pentan-2-amine

Part A:(S)-1-((6-bromo-4-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

To a 20 mL pressure vial was added (S)-2-amino-2,4-dimethylpentan-1-ol(323 mg, 2.462 mmol) and 2-bromo-5-fluoro-4-(trifluoromethyl)pyridine(601 mg, 2.462 mmol) in tetrahydrofuran (3.3 mL) to give a tan solution.Potassium tert-butoxide (2.95 mL, 2.95 mmol) (1.0 M in THF) was addeddropwise under nitrogen. After 5 min stirring at rt, the vial was sealedand the mixture was stirred at 80° C. for 18 h. The mixture waspartitioned between water and EtOAc. The layers were separated. Theaqueous layer was extracted with EtOAc. The combined organic solutionwas washed with brine, dried and concentrated to a tan oil. The crudewas purified by silica gel chromatography up to 10% MeOH/CH₂Cl₂ toafford(S)-1-((6-bromo-4-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(0.42 g, 48%) as a tan oil: ¹H NMR (400 MHz, Chloroform-d) δ 8.19 (s,1H), 7.64 (s, 1H), 3.95-3.86 (m, 2H), 1.80 (dt, J=12.8, 6.4 Hz, 1H),1.65 (s, 2H), 1.50 (dd, J=5.7, 4.0 Hz, 2H), 1.25 (s, 3H), 0.99 (dd,J=9.1, 6.6 Hz, 6H); ⁹F NMR (376 MHz, Chloroform-d) δ −64.37; LCMS (ESI)m/e 338.0 [(M+H)⁺, calcd C₁₃H₁₆BrF₃NO, 338.1]; LC/MS retention time(method B): t_(R)=1.88 min.

Part B:(S)-2,4-dimethyl-1-((2′-methyl-4-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)pentan-2-amine

Prepared as described in Example 117 to afford(S)-2,4-dimethyl-1-((2′-methyl-4-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)pentan-2-amine(25.2 mg, 0.066 mmol, 61% yield): ¹H NMR (500 MHz, DMSO-d₆) δ 8.79 (s,1H), 8.55 (d, J=5.2 Hz, 1H), 8.28 (s, 1H), 7.96 (s, 1H), 7.87 (d, J=5.4Hz, 1H), 4.05 (d, J=5.5 Hz, 2H), 2.56 (s, 3H), 1.81 (dt, J=12.6, 6.3 Hz,1H), 1.45-1.33 (m, 2H), 1.12 (s, 3H), 0.92 (dd, J=6.6, 3.0 Hz, 6H); LCMS(ESI) m/e 368.2 (M+H)⁺, calcd C₁₉H₂₅F₃N₃O, 368.2]; LC/MS retention time(method B): t_(R)=1.48 min.

Example 145(S)-2,4-dimethyl-1-((6-(quinolin-4-yl)-4-(trifluoromethyl)pyridin-3-yl)oxy)pentan-2-amine

Prepared as described in Example 117 to afford(S)-2,4-dimethyl-1-((6-(quinolin-4-yl)-4-(trifluoromethyl)pyridin-3-yl)oxy)pentan-2-amine(16.2 mg, 0.038 mmol, 58% yield): ¹H NMR (500 MHz, DMSO-d₆) δ 9.01 (d,J=4.6 Hz, 1H), 8.92 (s, 1H), 8.17 (d, J=8.3 Hz, 1H), 8.13 (d, J=8.5 Hz,1H), 8.03 (s, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.70 (d, J=4.4 Hz, 1H), 7.64(t, J=7.7 Hz, 1H), 4.20 (d, J=3.9 Hz, 2H), 1.84 (d, J=10.3 Hz, 1H), 1.50(qd, J=14.1, 5.5 Hz, 2H), 1.23 (s, 3H), 0.95 (t, J=6.1 Hz, 6H); LCMS(ESI) m/e 404.2 (M+H)⁺, calcd C₂₂H₂₅F₃N₃O, 404.2]; LC/MS retention time(method B): t_(R)=1.71 min.

Example 146 (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-(trifluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate

Prepared as described in Example 117 to afford (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-(trifluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate(4.4 mg, 0.010 mmol, 18% yield): ¹H NMR (500 MHz, DMSO-d₆) δ 10.31 (s,1H), 8.82 (s, 1H), 8.55 (s, 1H), 8.37 (d, J=5.5 Hz, 1H), 8.18 (s, 1H),7.74 (d, J=5.4 Hz, 1H), 4.12-3.99 (m, 2H), 3.71 (s, 3H−under solventpeak), 1.81 (dt, J=13.2, 6.6 Hz, 1H), 1.39 (d, J=5.6 Hz, 2H), 1.12 (s,3H), 0.92 (dd, J=6.6, 2.9 Hz, 6H); LCMS (ESI) m/e 449.2 (M+Na)⁺, calcdC₂₀H₂₅F₃N₄NaO₃, 449.2]; LC/MS retention time (method B): t_(R)=1.79 min.

Example 147(S)-1-((2′-chloro-4-(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 117 with intermediate asdescribed in Example 120 and (2-chloro-pyridin-4-yl)boronic acid toafford(S)-1-((2′-chloro-4-(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(13.5 mg, 53%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.51 (d, J=5.2Hz, 1H), 8.30 (s, 1H), 8.17 (s, 1H), 8.09 (d, J=5.3 Hz, 1H), 7.33 (t,J=53.8 Hz, 1H), 4.03 (s, 2H), 1.80 (p, J=6.2 Hz, 1H), 1.41 (qd, J=14.0,5.5 Hz, 2H), 1.14 (s, 3H), 0.92 (dd, J=13.2, 6.6 Hz, 6H); LCMS (ESI) m/e370.1 [(M+H)⁺, calcd C₁₈H₂₃ClF₂N₃O, 370.1]; LC/MS retention time (methodB): t_(R)=1.91 min.

Example 148(S)-1-((4-(difluoromethyl)-5′-fluoro-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

To a 2 mL vial was added(S)-1-((2′-chloro-4-(difluoromethyl)-5′-fluoro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(Example 143) (7.42 mg, 0.019 mmol),2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.402 mg, 0.019 mmol),and Cs₂CO₃ (9.35 mg, 0.029 mmol) in dioxane (0.2 mL) and water (0.1 mL)to give a colorless suspension under nitrogen (degassed for 5 min).1,1′-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride, toluene(0.787 mg, 0.957 μmol) was added under nitrogen. The vial was sealed andheated at 100° C. for 20 h. The mixture was dried, and diluted withMeOH, filtered and purified by prep-HPLC to afford(S)-1-((4-(difluoromethyl)-5′-fluoro-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(1.8 mg, 26%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.73 (s, 1H), 8.54 (d, J=2.9Hz, 1H), 7.99 (s, 1H), 7.80 (d, J=6.5 Hz, 1H), 7.38 (t, J=53.9 Hz, 1H),4.12-4.02 (m, 2H), 2.54 (s, 3H), 1.79 (dq, J=12.6, 6.2 Hz, 1H), 1.44(qd, J=14.0, 5.6 Hz, 2H), 1.17 (s, 3H), 0.94 (d, J=6.6 Hz, 3H), 0.91 (d,J=6.6 Hz, 3H); LCMS (ESI) m/e 351.1 [(M-NH₂)+, calcd C₁₉H₂₂F₃N₂O,351.2]; LC/MS retention time (method B): t_(R)=1.81 min.

Example 149(S)-1-((4-(difluoromethyl)-3′-fluoro-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 148 with Example 142 as thestarting material to afford(S)-1-((4-(difluoromethyl)-3′-fluoro-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(2.0 mg, 25%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.39 (d, J=5.1Hz, 1H), 8.01 (s, 1H), 7.77 (t, J=5.5 Hz, 1H), 7.38 (t, J=53.9 Hz, 1H),4.06 (d, J=3.0 Hz, 2H), 2.54 (d, J=3.4 Hz, 3H), 1.86-1.76 (m, 1H),1.50-1.37 (m, 2H), 1.17 (s, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.7Hz, 3H); LCMS (ESI) m/e 351.1 [(M-NH₂)+, calcd C₁₉H₂₂F₃N₂O, 351.2];LC/MS retention time (method B): t_(R)=1.78 min.

Example 150(S)-1-((4-(difluoromethyl)-6-(2-methylpyrimidin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 132 to afford(S)-1-((4-(difluoromethyl)-6-(2-methylpyrimidin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(0.8 mg, 2.3% for 2 steps) as a colorless solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.83 (d, J=5.2 Hz, 1H), 8.71 (s, 1H), 8.53 (s, 1H), 8.10 (d,J=5.2 Hz, 1H), 7.41 (s, 1H), 4.08 (d, J=2.2 Hz, 2H), 2.72 (s, 3H), 1.81(dt, J=12.9, 6.5 Hz, 1H), 1.44 (qd, J=14.0, 5.5 Hz, 2H), 1.17 (s, 3H),0.95 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.7 Hz, 3H); LCMS (ESI) m/e 334.1[(M-NH₂)+, calcd C₁₈H₂₂F₂N₃O, 334.2]; LC/MS retention time (method B):t_(R)=1.83 min.

Example 152(S)-1-(2-(difluoromethyl)-4-(2-methylpyrimidin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 116 with4-bromo-2-methylpyrimidine to afford(S)-1-(2-(difluoromethyl)-4-(2-methylpyrimidin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine(32.2 mg, 56% for 2 steps) as a colorless solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.72 (d, J=5.4 Hz, 1H), 8.38 (d, J=2.2 Hz, 1H), 8.35 (dd,J=8.8, 2.3 Hz, 1H), 7.89 (d, J=5.4 Hz, 1H), 7.43-7.16 (m, 2H), 3.87 (s,2H), 2.68 (s, 3H), 1.80 (dp, J=12.8, 6.3 Hz, 1H), 1.48-1.35 (m, 2H),1.14 (s, 3H), 0.93 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.7 Hz, 3H); LCMS (ESI)m/e 333.2 [(M-NH₂)+, calcd C₁₉H₂₃F₂N₂O, 333.2]; LC/MS retention time(method B): t_(R)=1.85 min.

Example 153(S)-5-((2-amino-2,4-dimethylpentyl)oxy)-3′-fluoro-6-methyl-[2,4′-bipyridin]-2′-amine

Part A: 6-iodo-2-methylpyridin-3-ol

To a 500 mL round-bottomed flask was added 2-methylpyridin-3-ol (4.0 g,36.7 mmol) and Na₂CO₃ (7.8 g, 73.6 mmol) in water (100 mL) to give aslightly tan solution/suspension. I₂ (9.6 g, 37.8 mmol) was added in oneportion. The mixture was stirred at rt for 3 h. There were noticeable I₂left. The mixture was stirred overnight and there was still I₂ left. Thereaction mixture was heated at 42° C. (bath temp) for 5 h (most I₂disappeared). The reaction was slowly neutralized with 1N HCl (150 mL)to pH-5. Precipitate was collected by filtration, rinsed with water,aqueous sodium bisulfite solution, and dried under vacuum to yield ayellowish gray powder (7 g). The solids were purified by silica gelchromatography up to 30% EtOAc/hexane to afford6-iodo-2-methylpyridin-3-ol (4.58 g, 53%) as a light yellow solid: ¹HNMR (400 MHz, Chloroform-d) δ 7.42 (dd, J=8.3, 0.7 Hz, 1H), 6.81 (d,J=8.3 Hz, 1H), 2.48 (s, 3H); LCMS (ESI) m/e 235.8 [(M+H)⁺, calcdC₆H₇INO, 236.0]; LC/MS retention time (method B): t_(R)=1.14 min.

Part B: (S)-tert-butyl(1-((6-iodo-2-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2 yl)carbamate

Prepared as previously described in Example 32 to afford (S)-tert-butyl(1-((6-iodo-2-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2 yl)carbamate(528 mg, 100%) as a tan oil: ¹H NMR (400 MHz, Chloroform-d) δ 7.46 (d,J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 4.53 (s, 1H), 4.14 (d, J=8.9 Hz,1H), 3.96 (d, J=8.9 Hz, 1H), 2.46 (s, 3H), 1.83 (tdt, J=13.2, 11.6, 6.5Hz, 2H), 1.53 (d, J=4.7 Hz, 1H), 1.40 (s, 9H), 1.39 (s, 3H), 1.00 (d,J=3.0 Hz, 3H), 0.98 (d, J=3.0 Hz, 3H); LCMS (ESI) m/e 448.9 [(M+H)⁺,calcd C₁₈H₃IN₂O₃, 449.1]; LC/MS retention time (method B): t_(R)=2.38min.

Part C:(S)-tert-butyl(1-((2′-chloro-3′-fluoro-6-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Prepared as previously described in Example 66 to afford (S)-tert-butyl(1-((2′-chloro-3′-fluoro-6-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(18.9 mg, 17%): LCMS (ESI) m/e 452.2 [(M+H)⁺, calcd C₂₃H₃₂ClFN₃O₃,452.2]; LC/MS retention time (method B): t_(R)=2.46 min.

Part D: (S)-tert-butyl(1-((2′-amino-3′-fluoro-6-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

To a 20 mL pressure vial was added (S)-tert-butyl(1-((2′-chloro-3′-fluoro-6-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(18.9 mg, 0.042 mmol), and methyl carbamate (4.39 mg, 0.059 mmol) in1,4-dioxane (0.4 mL) to give a colorless solution. While degassing,PdOAc₂ (0.939 mg, 4.18 μmol), XANTPHOS (4.84 mg, 8.36 μmol), Cs₂CO₃(20.44 mg, 0.063 mmol) were added.

The vial was sealed under nitrogen and heated at 90° C. for 20 h. LCMSshowed partial conversion but the carbamate was completely hydrolyzed.The mixture was diluted with EtOAc, dried, filtered, and concentrated.The residue (containing a mixture of the starting material chloride andthe hydrolyzed amine product) was directly used in the next step. Theamine: LCMS (ESI) m/e 433.3 (M+H)⁺, calcd C₂₃H₃₄FN₄O₃, 433.3]; LC/MSretention time (method B): t_(R)=1.99 min; The chloride: LCMS (ESI) m/e452.1 [(M+H)⁺, calcd C₂₃H₃₂ClFN₃O₃, 452.2]; LC/MS retention time (methodB): t_(R)=2.48 min.

Part E:(S)-5-((2-amino-2,4-dimethylpentyl)oxy)-3′-fluoro-6-methyl-[2,4′-bipyridin]-2′-amine

Prepared as previously described in Example 7, Part B to afford amixture of the amine and chloride. The mixture was purified by prep-HPLCto afford(S)-5-((2-amino-2,4-dimethylpentyl)oxy)-3′-fluoro-6-methyl-[2,4′-bipyridin]-2′-amine(4.3 mg, 31% for 2 steps): ¹H NMR (500 MHz, DMSO-d₆) δ 7.79 (d, J=5.3Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.02 (t, J=5.2Hz, 1H), 6.22 (s, 2H), 3.86 (s, 2H), 2.50 (s, 3H), 1.81 (dq, J=12.8, 6.5Hz, 1H), 1.56-1.42 (m, 2H), 1.21 (s, 3H), 0.94 (dd, J=10.3, 6.7 Hz, 6H);LCMS (ESI) m/e 333.2 [(M+H)⁺, calcd C₁₈H₂₆FN₄O, 333.2]; LC/MS retentiontime (method B): t_(R)=1.48 min.

Example 154(S)-1-((2′-chloro-3′-fluoro-6-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((2′-amino-3′-fluoro-6-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Obtained as a mixture with the amine from Example 153, Part D. LCMS(ESI) m/e 452.1 [(M+H)⁺, calcd C₂₃H₃₂ClFN₃O₃, 452.2]; LC/MS retentiontime (method B): t_(R)=2.48 min.

Part B:(S)-1-((2′-chloro-3′-fluoro-6-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

The crude mixture from Example 153, Part D was deprotected as previouslydescribed in Example 7, Part B to afford a mixture of the amine andchloride. The mixture was separated and purified by prep-HPLC to afford(S)-1-((2′-chloro-3′-fluoro-6-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine:(2.6 mg, 17% for 2 steps): ¹H NMR (500 MHz, DMSO-d₆) δ 8.33 (d, J=5.0Hz, 1H), 7.99 (t, J=5.3 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.49 (d, J=8.6Hz, 1H), 3.83 (s, 2H), 2.51 (s, 3H−OCH3 protons under DMSOpeak−predicted shift=2.47 ppm), 1.82 (p, J=6.2 Hz, 1H), 1.53-1.38 (m,2H), 1.18 (s, 3H), 0.94 (t, J=7.2 Hz, 6H); LCMS (ESI) m/e 335.1[(M-NH₂)+, calcd C₁₈H₂₁ClFN₂O, 335.1]; LC/MS retention time (method B):t_(R)=1.91 min.

Example 155 (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-5′-fluoro-6-methyl-[2,4′-bipyridin]-2′-yl)carbamate

Part A: (S)-tert-butyl(1-((2′-chloro-5′-fluoro-6-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Prepared as previously described in Example 66 with intermediate fromExample 153 and (2-chloro-5-fluoro-pyridin-4yl)boronic acid to afford(S)-tert-butyl(1-((2′-chloro-5′-fluoro-6-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(13.4 mg, 13%): LCMS (ESI) m/e 452.1 [(M+H)⁺, calcd C₂₃H₃₂ClFN₃O₃,452.2]; LC/MS retention time (method B): t_(R)=2.49 min.

Part B: (S)-methyl(5-((2-Boc-amino-2,4-dimethylpentyl)oxy)-5′-fluoro-6-methyl-[2,4′-bipyridin]-2′-yl)carbamate

Prepared as previously described in Example 153 to afford (S)-methyl(5-((2-Boc-amino-2,4-dimethylpentyl)oxy)-5′-fluoro-6-methyl-[2,4′-bipyridin]-2′-yl)carbamate(no carbamate hydrolysis observed) contaminated with left over startingmaterial ((S)-tert-butyl(1-((2′-chloro-5′-fluoro-6-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate).The crude mixture was carried on without further purification.Carbamate: LCMS (ESI) m/e 491.2 (M+H)⁺, calcd C₂₅H₃₆FN₄O₅, 491.3]; LC/MSretention time (method B): t_(R)=2.30 min.

Part C: (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-5′-fluoro-6-methyl-[2,4′-bipyridin]-2′-yl)carbamate

Prepared as previously described in Example 7, Part B. The crude mixturewas separated and purified by prep-HPLC to afford (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-5′-fluoro-6-methyl-[2,4′-bipyridin]-2′-yl)carbamate(0.3 mg, 2.5% for 2 steps) as a colorless solid. ¹H NMR (400 MHz,Methanol-d₄) δ 8.45 (d, J=5.9 Hz, 1H), 8.21 (d, J=2.7 Hz, 1H), 7.79-7.73(m, 1H), 7.46 (d, J=8.6 Hz, 1H), 4.07-3.96 (m, 2H), 3.80 (s, 3H), 2.61(s, 3H), 1.87 (dt, J=12.5, 6.4 Hz, 1H), 1.73 (dd, J=14.3, 5.6 Hz, 1H),1.62 (dd, J=14.2, 5.5 Hz, 1H), 1.39 (s, 3H), 1.04 (dd, J=10.9, 6.6 Hz,6H); LCMS (ESI) m/e 391.4 [(M+H)⁺, calcd C₂₀H₂₈FN₄O₃, 391.2].

Example 156(S)-1-((2′-chloro-5′-fluoro-6-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Part C:(S)-1-((2′-chloro-5′-fluoro-6-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Recovered from mixture obtained in Example 155, Part C. The mixture wasseparated and purified by prep-HPLC to afford(S)-1-((2′-chloro-5′-fluoro-6-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(5.2 mg, 49% for 2 steps) as a colorless solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.54 (d, J=2.6 Hz, 1H), 8.03 (d, J=5.5 Hz, 1H), 7.83 (d,J=8.4 Hz, 1H), 7.48 (d, J=8.6 Hz, 1H), 3.81 (s, 2H), 2.51 (s, 3H−OCH3protons under DMSO peak−predicted shift=2.47 ppm), 1.81 (dq, J=12.6, 6.5Hz, 1H), 1.49-1.36 (m, 2H), 1.16 (s, 3H), 0.93 (t, J=6.3 Hz, 6H); LCMS(ESI) m/e 335.1 [(M-NH₂)+, calcd C₁₈H₂₁ClFN₂O, 335.1]; LC/MS retentiontime (method B): t_(R)=1.93 min.

Example 157 (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-3′-fluoro-6-methyl-[2,4′-bipyridin]-2′-yl)carbamate

Part A: (S)-methyl(5-((2-Boc-amino-2,4-dimethylpentyl)oxy)-3′-fluoro-6-methyl-[2,4′-bipyridin]-2′-yl)carbamate

Prepared as previously described in Example 153 with reaction running at80° C. for 30 h resulting in the carbamate after prep-HPLC purification(7.1 mg, 19%): LCMS (ESI) m/e 491.4 (M+H)⁺, calcd C₂₅H₃₆FN₄O₅, 491.3];LC/MS retention time (method A): t_(R)=1.99 min.

Part B: (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-3′-fluoro-6-methyl-[2,4′-bipyridin]-2′-yl)carbamate

Prepared as previously described in Example 7, Part B to afford(S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-3′-fluoro-6-methyl-[2,4′-bipyridin]-2′-yl)carbamate(5.2 mg, 90%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.25 (d, J=5.1 Hz, 1H), 7.79(t, J=5.2 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 3.80(s, 2H), 3.68 (s, 3H), 2.50 (s, 3H), 1.81 (dt, J=12.5, 6.5 Hz, 1H),1.48-1.38 (m, 2H), 1.15 (s, 3H), 0.93 (t, J=6.3 Hz, 6H); LCMS (ESI) m/e413.1 [(M+Na)⁺, calcd C₂₀H₂₇FN₄NaO₃, 413.2]; LC/MS retention time(method B): t_(R)=1.66 min.

Example 158(S)-1-((2′-chloro-6-(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 117 with (2-chloropyridin-4-yl)boronicacid to afford(S)-1-((2′-chloro-6-(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(26.3 mg, 0.068 mmol, 49%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.52 (d, J=5.2Hz, 1H), 8.37 (d, J=8.8 Hz, 1H), 8.13 (s, 1H), 8.07 (d, J=5.2 Hz, 1H),7.81 (d, J=8.8 Hz, 1H), 7.27 (t, J=53.6 Hz, 1H), 3.94 (s, 2H), 1.79 (dt,J=12.6, 6.4 Hz, 1H), 1.43 (qd, J=14.1, 5.6 Hz, 2H), 1.16 (s, 3H), 0.92(dd, J=12.8, 6.6 Hz, 6H); LCMS (ESI) m/e 370.1 [(M+H)⁺, calcdC₁₉H₂₆F₂N₃O, 370.1]; LC/MS retention time (method B): t_(R)=1.91 min.

Example 159(S)-1-((2′-chloro-6-(difluoromethyl)-3′-fluoro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 117 with(2-chloro-3-fluoropyridin-4-yl)boronic acid to afford(S)-1-((2′-chloro-6-(difluoromethyl)-3′-fluoro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(25 mg, 0.064 mmol, 9.6%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.38 (dd, J=5.3,2.4 Hz, 1H), 8.12 (d, J=8.9 Hz, 1H), 7.96 (td, J=5.3, 2.2 Hz, 1H), 7.83(d, J=8.8 Hz, 1H), 7.25 (t, J=53.5 Hz, 1H), 3.91 (d, J=2.0 Hz, 2H),1.86-1.75 (m, 1H), 1.40 (t, J=6.2 Hz, 2H), 1.14 (d, J=2.2 Hz, 3H), 0.92(ddd, J=9.7, 6.8, 2.3 Hz, 6H); LCMS (ESI) m/e 388.1 [(M+H)⁺, calcdC₁₈H₂₂ClF₃N₃O, 388.1]; LC/MS retention time (method B): t_(R)=1.94 min.

Example 160(S)-1-((6-(difluoromethyl)-3′-fluoro-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 148 to afford(S)-1-((6-(difluoromethyl)-3′-fluoro-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(12.8 mg, 0.033 mmol, 55%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.39 (d, J=5.0Hz, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.75 (t, J=5.5Hz, 1H), 7.24 (t, J=53.5 Hz, 1H), 3.92 (s, 2H), 2.54 (d, J=3.3 Hz, 3H),1.80 (dt, J=12.6, 6.3 Hz, 1H), 1.50-1.36 (m, 2H), 1.15 (s, 3H), 0.92(dd, J=11.5, 6.6 Hz, 6H); LCMS (ESI) m/e 368.2 [(M+H)⁺, calcdC₁₉H₂₅F₃N₃O, 368.2]; LC/MS retention time (method B): t_(R)=1.72 min.

Example 161((S)-1-((6-chloro-2′-(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((6-chloro-2′-(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Prepared as previously described in Example 66 with intermediates iodideas described in Example 66 and (2-(difluoromethyl)pyridin-4-yl)boronicacid as described in Example 123 (concentrated to dryness and used asis) to afford (S)-tert-butyl(1-((6-chloro-2′-(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(70 mg, 19%): ¹H NMR (400 MHz, Chloroform-d) δ 8.74 (d, J=5.2 Hz, 1H),8.18 (d, J=1.7 Hz, 1H), 8.04-7.97 (m, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.38(d, J=8.5 Hz, 1H), 6.73 (t, J=55.5 Hz, 1H), 4.59 (s, 1H), 4.38 (d, J=8.9Hz, 1H), 4.18 (d, J=8.8 Hz, 1H), 1.99-1.81 (m, 2H), 1.57-1.52 (m, 1H),1.46 (s, 3H), 1.40 (s, 9H), 1.03 (d, J=6.6 Hz, 6H); ¹⁹F NMR (376 MHz,Chloroform-d) δ −115.83; LCMS (ESI) m/e 470.2 (M+H)⁺, calcdC₂₃H₃₁ClF₂N₃O₃, 470.2]; LC/MS retention time (method A): t_(R)=2.50 min.

Part B:((S)-1-((6-chloro-2′-(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 7, Part B to afford((S)-1-((6-chloro-2′-(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(40.6 mg, 74%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.77 (d, J=5.1 Hz, 1H), 8.22(d, J=8.1 Hz, 2H), 8.13 (d, J=5.2 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.01(t, J=55.0 Hz, 1H), 3.92 (s, 2H), 1.79 (dt, J=12.5, 6.6 Hz, 1H), 1.44(qd, J=14.1, 5.5 Hz, 2H), 1.16 (s, 3H), 0.91 (t, J=6.2 Hz, 6H); ¹⁹F NMR(376 MHz, DMSO-d6) δ −115.46 (d, J=55.0 Hz); LCMS (ESI) m/e 392.1[(M+Na)⁺, calcd C₁₈H₂₂ClF₂N₃NaO, 392.1]; LC/MS retention time (methodB): t_(R)=1.94 min.

Example 162(S)-1-((4-(difluoromethyl)-6-(6-methylpyridazin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 117 with3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine toafford(S)-1-((4-(difluoromethyl)-6-(6-methylpyridazin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(23.6 mg, 0.066 mmol, 48%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.72 (d, J=2.1Hz, 1H), 8.72 (s, 1H), 8.34 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.35 (t,J=54.0 Hz, 1H), 4.04 (s, 2H), 2.71 (s, 3H), 1.85-1.74 (m, 1H), 1.42 (qd,J=13.7, 5.3 Hz, 2H), 1.15 (s, 3H), 0.92 (dd, J=13.3, 6.7 Hz, 6H); LCMS(ESI) m/e 373.2 [(M+Na)⁺, calcd C₁₈H₂₄F₂N₄NaO, 373.2]; LC/MS retentiontime (method B): t_(R)=1.59 min.

Example 163(S)-1-((2-(difluoromethyl)-6-(6-methylpyridazin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 117 with3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine toafford(S)-1-((2-(difluoromethyl)-6-(6-methylpyridazin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(37.2 mg, 0.105 mmol, 85%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.71 (d, J=2.1Hz, 1H), 8.40 (d, J=8.8 Hz, 1H), 8.13 (d, J=2.1 Hz, 1H), 7.84 (d, J=8.9Hz, 1H), 7.24 (t, J=53.6 Hz, 1H), 3.91 (s, 2H), 2.71 (s, 3H), 1.80 (dt,J=13.2, 6.3 Hz, 1H), 1.46-1.34 (m, 2H), 1.13 (s, 3H), 0.92 (dd, J=10.5,6.6 Hz, 6H); LCMS (ESI) m/e 373.2 [(M+Na)⁺, calcd C₁₈H₂₄F₂N₄NaO, 373.2];LC/MS retention time (method B): t_(R)=1.62 min.

Example 164

(R)-2,4-dimethyl-1-((2′-methyl-4-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)pentan-2-amine

Part A:(R)-1-((6-bromo-4-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 144 with R-enantiomer of theamino alcohol to afford(R)-1-((6-bromo-4-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(0.58 g, 97%) as a tan oil: ¹H NMR (400 MHz, Chloroform-d) δ 8.19 (s,1H), 7.64 (s, 1H), 3.97-3.83 (m, 2H), 1.85-1.73 (m, 1H), 1.49 (dd,J=5.7, 4.0 Hz, 2H), 1.24 (s, 3H), 0.99 (dd, J=9.3, 6.6 Hz, 6H); ¹⁹F NMR(376 MHz, Chloroform-d) δ −64.39; LCMS (ESI) m/e 338.0 [(M+H)⁺, calcdC₁₃H₁₆BrF₃NO, 338.1]; LC/MS retention time (method B): t_(R)=1.87 min.

Part B:(R)-2,4-dimethyl-1-((2′-methyl-4-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)pentan-2-amine

Prepared as described in Example 144 to afford(R)-2,4-dimethyl-1-((2′-methyl-4-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)pentan-2-amine(7.6 mg, 0.020 mmol, 23% yield): ¹H NMR (500 MHz, DMSO-d₆) δ 8.79 (s,1H), 8.55 (d, J=5.2 Hz, 1H), 8.29 (s, 1H), 7.97 (s, 1H), 7.88 (d, J=5.2Hz, 1H), 4.11-4.02 (m, 2H), 2.56 (s, 3H), 1.81 (dt, J=12.9, 6.5 Hz, 1H),1.40 (dd, J=5.6, 2.8 Hz, 2H), 1.13 (s, 3H), 0.92 (dd, J=6.6, 3.2 Hz,6H); LCMS (ESI) m/e 368.2 (M+H)⁺, calcd C₁₉H₂₅F₃N₃O, 368.2]; LC/MSretention time (method B): t_(R)=1.44 min.

Example 165(R)-2,4-dimethyl-1-((6-(quinolin-4-yl)-4-(trifluoromethyl)pyridin-3-yl)oxy)pentan-2-amine

Prepared as described in Example 144 to afford(R)-2,4-dimethyl-1-((6-(quinolin-4-yl)-4-(trifluoromethyl)pyridin-3-yl)oxy)pentan-2-amine(14.9 mg, 0.037 mmol, 45% yield): ¹H NMR (500 MHz, DMSO-d₆) δ 9.01 (d,J=4.4 Hz, 1H), 8.90 (s, 1H), 8.18 (d, J=8.5 Hz, 1H), 8.13 (d, J=8.5 Hz,1H), 8.02 (s, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.70 (d, J=4.4 Hz, 1H), 7.64(t, J=7.7 Hz, 1H), 4.15-4.05 (m, 2H), 1.83 (dq, J=12.6, 6.3 Hz, 1H),1.42 (dd, J=5.7, 2.0 Hz, 2H), 1.16 (s, 3H), 0.95 (dd, J=6.6, 3.5 Hz,6H); LCMS (ESI) m/e 404.2 (M+H)⁺, calcd C₂₂H₂₅F₃N₃O, 404.2]; LC/MSretention time (method B): t_(R)=1.66 min.

Example 166 (R)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-(trifluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate

Prepared as described in Example 144 to afford (R)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-(trifluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate(7.8 mg, 0.018 mmol, 35% yield): ¹H NMR (500 MHz, DMSO-d₆) δ 8.81 (s,1H), 8.54 (s, 1H), 8.37 (d, J=5.2 Hz, 1H), 8.18 (s, 1H), 7.74 (dd,J=5.3, 1.6 Hz, 1H), 4.10-4.00 (m, 2H), 3.71 (s, 3H), 1.81 (hept, J=6.1Hz, 1H), 1.41-1.34 (m, 2H), 1.12 (s, 3H), 0.92 (dd, J=6.8, 2.7 Hz, 6H);LCMS (ESI) m/e 449.1 (M+Na)⁺, calcd C₂₀H₂₅F₃N₄NaO₃, 449.2]; LC/MSretention time (method B): t_(R)=1.72 min.

Example 167(R)-1-((2′-chloro-4-(difluoromethyl)-3′-fluoro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Part A:(R)-1-((6-bromo-4-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 142 with R-enantiomer of theamino alcohol to afford(R)-1-((6-bromo-4-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(740 mg, 95%): LCMS (ESI) m/e 336.9 [(M+H)⁺, calcd C₁₃H₂₀BrF₂N₂O,337.1]; LC/MS retention time (method B): t_(R)=1.83 min. The materialwas used as is.

Prepared as previously described in Example 142 with intermediate asdescribed above and (2-chloro-3-fluoro-pyridin-4-yl)boronic acid (6.7mg, 11%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.38 (d, J=5.0 Hz,1H), 8.06 (s, 1H), 7.97 (t, J=5.4 Hz, 1H), 7.38 (t, J=53.9 Hz, 1H), 4.05(s, 2H), 1.81 (dt, J=12.9, 6.4 Hz, 1H), 1.42 (tt, J=14.1, 6.8 Hz, 2H),1.15 (d, J=3.5 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H);LCMS (ESI) m/e 371.1 [(M-NH₂)+, calcd C₁₈H₁₉ClF₃N₂O, 371.1]; LC/MSretention time (method B): t_(R)=2.02 min.

Example 168(R)-1-((2′-chloro-4-(difluoromethyl)-5′-fluoro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 142 with intermediate asdescribed in Example 167 and (2-chloro-5-fluoro-pyridin-4-yl)boronicacid to afford(R)-1-((2′-chloro-4-(difluoromethyl)-5′-fluoro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(14 mg, 20%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.75 (s, 1H), 8.60 (d, J=2.3Hz, 1H), 8.05 (s, 1H), 8.02 (d, J=5.5 Hz, 1H), 7.36 (t, J=53.9 Hz, 1H),4.04 (s, 2H), 1.81 (hept, J=6.4 Hz, 1H), 1.48-1.35 (m, 2H), 1.14 (d,J=3.3 Hz, 3H), 0.93 (dd, J=12.6, 6.6 Hz, 6H); LCMS (ESI) m/e 371.1[(M-NH₂)+, calcd C₁₈H₁₉ClF₃N₂O, 371.1]; LC/MS retention time (method B):t_(R)=1.98 min.

Example 169(R)-1-((2′-chloro-4-(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 142 with intermediate asdescribed in Example 167 and (2-chloro-pyridin-4-yl)boronic acid toafford(R)-1-((2′-chloro-4-(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(10.2 mg, 49%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.70 (s, 1H), 8.51 (d, J=5.3Hz, 1H), 8.31 (s, 1H), 8.18 (s, 1H), 8.11 (d, J=5.3 Hz, 1H), 7.33 (t,J=53.9 Hz, 1H), 4.02 (s, 2H), 1.80 (q, J=6.3 Hz, 1H), 1.40 (tt, J=14.0,7.4 Hz, 2H), 1.14 (s, 3H), 0.93 (dd, J=12.5, 6.6 Hz, 6H); LCMS (ESI) m/e353.1 [(M-NH₂)+, calcd C₁₈H₂₀ClF₂N₂O, 353.1]; LC/MS retention time(method B): t_(R)=1.90 min.

Example 170(R)-1-((4-(difluoromethyl)-2′-ethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 141 with intermediate asdescribed in Example 167 and (2-ethylpyridin-4-yl)boronic acid to afford(R)-1-((4-(difluoromethyl)-2′-ethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(12.3 mg, 60%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.57 (d, J=5.3Hz, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 7.88-7.84 (m, 1H), 7.35 (t, J=53.9Hz, 1H), 4.02 (s, 2H), 2.84 (q, J=7.6 Hz, 2H), 1.81 (dt, J=12.7, 6.5 Hz,1H), 1.42 (qd, J=14.0, 5.5 Hz, 2H), 1.29 (t, J=7.6 Hz, 3H), 1.15 (s,3H), 0.93 (dd, J=13.5, 6.6 Hz, 6H); LCMS (ESI) m/e 364.2 [(M+H)⁺, calcdC₂H₂₈F₂N₃O, 364.2]; LC/MS retention time (method B): t_(R)=1.48 min.

Example 171(R)-1-((4-(difluoromethyl)-5′-fluoro-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 148 with Example 168 toafford(R)-1-((4-(difluoromethyl)-5′-fluoro-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(1.2 mg, 10%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.55 (d, J=2.9Hz, 1H), 7.99 (s, 1H), 7.81 (d, J=6.5 Hz, 1H), 7.40 (t, J=53.8 Hz, 1H),4.15-4.05 (m, 2H), 2.54 (s, 3H), 1.81 (dt, J=12.8, 6.3 Hz, 1H),1.54-1.39 (m, 2H), 1.19 (s, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6Hz, 3H); LCMS (ESI) m/e 351.1 [(M-NH₂)+, calcd C₁₉H₂₂F₃N₂O, 351.2];LC/MS retention time (method B): t_(R)=1.80 min.

Example 172(R)-1-((4-(difluoromethyl)-3′-fluoro-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 148 with Example 167 as thestarting material to afford(R)-1-((4-(difluoromethyl)-3′-fluoro-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(1.1 mg, 24%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.40 (d, J=5.0Hz, 1H), 8.02 (s, 1H), 7.77 (t, J=5.5 Hz, 1H), 7.43 (t, J=53.9 Hz, 1H),4.13 (q, J=9.5 Hz, 2H), 2.54 (d, J=3.3 Hz, 3H), 1.81 (dt, J=12.9, 6.4Hz, 1H), 1.57-1.41 (m, 2H), 1.22 (s, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.92(d, J=6.6 Hz, 3H); LCMS (ESI) m/e 351.1 [(M-NH₂)+, calcd C₁₉H₂₂F₃N₂O,351.2]; LC/MS retention time (method B): t_(R)=1.79 min.

Example 173 (R)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-6-methyl-[2,4′-bipyridin]-2′-yl)carbamate

Prepared as previously described in Example 164 using the R-enantiomerof the amino alcohol to afford (R)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-6-methyl-[2,4′-bipyridin]-2′-yl)carbamate(26 mg, 0.050 mmol, 26%) as a pale yellow film. ¹H NMR (400 MHz,MeOH-d₄) δ 8.36 (d, J=6.5 Hz, 1H), 8.24 (d, J=1.3 Hz, 1H), 8.05 (m, 2H),7.58 (d, J=8.5 Hz, 1H), 4.25 (m, 2H), 3.94 (s, 3H), 3.38 (s, 2H), 2.66(s, 3H), 1.95-1.85 (m, 2H), 1.81-1.71 (m, 1H), 1.55 (s, 3H), 1.09 (d,J=6.5 Hz, 3H), 1.04 (d, J=6.4 Hz, 3H); LCMS (ESI) m/e 373.4 (M+H)⁺,calcd C₂₀H₂₉N₄O₃, 373.2]; LC/MS retention time (method D): t_(R)=1.81min.

Example 174(R)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 123 using the R-enantiomerof the amino alcohol to afford(R)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(6.6 mg, 0.017 mmol, 15%) as a film. ¹H NMR (500 MHz, DMSO-d₆) δ 8.79(d, J=5.1 Hz, 1H), 8.40 (d, J=8.8 Hz, 1H), 8.33 (s, 1H), 8.22 (d, J=5.1Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.25 (t, J=53.5 Hz, 1H), 7.05 (t,J=54.9 Hz, 1H), 3.91 (s, 2H), 3.36 (m 2H), 1.81 (m, 1H), 1.40 (m, 2H),1.13 (s, 3H) 0.94 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.4 Hz, 3H); LCMS (ESI)m/e 386.4 (M+H)⁺, calcd C₁₉H₂₄F₄N₃O, 386.2]; LC/MS retention time(method D): t_(R)=2.62 min.

Example 175(R)-1-((2′,4-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as previously described in Example 124 using the R-enantiomerof the amino alcohol to afford(R)-1-((2′,4-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(9.3 mg, 0.024 mmol, 21%) as a film. ¹H NMR (500 MHz, DMSO-d₆) δ 8.79(d, J=5.1 Hz, 1H), 8.71 (s, 1H), 8.37 (s, 1H), 8.32 (s, 1H), 8.25 (d,J=4.8 Hz, 1H), 7.33 (t, J=53.5 Hz, 1H), 7.04 (t, J=54.9 Hz, 1H), 4.01(s, 2H), 3.32 (m, 2H), 1.81 (m, 1H), 1.40 (m, 2H), 1.13 (s, 3H) 0.94 (d,J=6.5 Hz, 3H), 0.92 (d, J=6.4 Hz, 3H); LCMS (ESI) m/e 386.4 (M+H)⁺,calcd C₁₉H₂₄F₄N₃O, 386.2]; LC/MS retention time (method D): t_(R)=2.66min.

Example 176(S)-1-((4-(difluoromethyl)-6-(quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-ol

Part A: (S)-2,4-dimethylpentane-1,2-diol

To a 500 mL round-bottomed flask was added AD-MIX-ALPHA (3.60 g, 2.60mmol) in BuOH (13 mL) and water (13 mL) to give a yellow solution undervigorously stirring. The resulting mixture was stirred at rt for 30 minand then cooled to 0° C. A precipitate appeared and2,4-dimethylpent-1-ene (0.364 mL, 2.60 mmol) was added in one portion.The resulting mixture was stirred vigorously at 0° C. for 6 h and 3.86 g(30.6 mmol) of sodium sulfite was added. The mixture was allowed to warmto rt and was stirred for 30 min. CH₂Cl₂ (40 mL) and water (80 mL) wasthen added successively and the layers were separated. The aqueous layerwas extracted twice with CH₂Cl₂. The combined organic phase was dried,filtered, and concentrated to afford (S)-2,4-dimethylpentane-1,2-diol(308 mg, 90%) as a colorless oil: ¹H NMR (400 MHz, Chloroform-d) δ3.52-3.38 (m, 2H), 1.85-1.79 (m, 1H), 1.42 (dd, J=6.0, 2.0 Hz, 2H), 1.22(s, 3H), 0.99 (dd, J=11.7, 6.6 Hz, 6H). Reference: S. J. Leiris et al.Bioorg. Med. Chem. 2010, 18, 3481-3493.

Part B:(S)-1-((6-bromo-4-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-ol

To a 20 mL pressure bottle was added (S)-2,4-dimethylpentane-1,2-diol(125 mg, 0.946 mmol) and 2-bromo-4-(difluoromethyl)-5-fluoropyridine(214 mg, 0.946 mmol) in tetrahydrofuran (1.3 mL) to give a tan solution.Potassium tert-butoxide (1.229 mL, 1.229 mmol) (1.0 M in THF) was addeddropwise under nitrogen. After 5 min stirring at rt, the bottle wassealed and the mixture was stirred at 80° C. for 18 h. The mixture waspartitioned between water and EtOAc. The layers were separated. Theaqueous layer was extracted with EtOAc. The combined organic solutionwas washed with brine, dried and concentrated to afford(S)-1-((6-bromo-4-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-ol(300 mg, 94%) as a tan oil. The material was used as is. LCMS (ESI) m/e338.0 [(M+H)⁺, calcd C₁₃H₁₉BrF₂NO₂, 338.0]; LC/MS retention time (methodB): t_(R)=2.30 min.

Part C:(S)-1-((4-(difluoromethyl)-6-(quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-ol

Prepared as previously described in Example 117 to afford(S)-1-((4-(difluoromethyl)-6-(quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-ol(3.6 mg, 14%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.00 (d, J=4.4 Hz, 1H), 8.80(s, 1H), 8.18 (d, J=8.4 Hz, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.87 (s, 1H),7.82 (t, J=7.7 Hz, 1H), 7.69-7.61 (m, 2H), 7.35 (s, 1H), 4.09 (q, J=9.2Hz, 2H), 1.86 (dt, J=12.7, 6.5 Hz, 1H), 1.50 (d, J=5.9 Hz, 2H), 1.27 (s,3H), 0.96 (d, J=6.5 Hz, 6H); LCMS (ESI) m/e 387.1 [(M+H)⁺, calcdC₂₂H₂₅F₂N₂O₂, 387.2]; LC/MS retention time (method B): t_(R)=2.06 min.

Example 177(S)-methyl(4-(difluoromethyl)-5-((2-hydroxy-2,4-dimethylpentyl)oxy)-[2,4′-bipyridin]-2′-yl)carbamate

Prepared as previously described in Example 117 with intermediate fromExample 176 (1.8 mg, 6.5%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.71 (s, 1H),8.53 (s, 1H), 8.36 (d, J=5.4 Hz, 1H), 8.07 (s, 1H), 7.77-7.67 (m, 1H),7.31 (s, 1H), 4.05 (q, J=9.3 Hz, 2H), 3.71 (s, 3H), 1.83 (dt, J=12.6,6.3 Hz, 1H), 1.47 (d, J=5.9 Hz, 2H), 1.24 (s, 3H), 0.94 (d, J=6.6 Hz,6H); LCMS (ESI) m/e 410.1 [(M+H)⁺, calcd C₂₀H₂₆F₂N₃O₄, 410.2]; LC/MSretention time (method B): t_(R)=2.07 min.

Example 178(S)-1-((4-(difluoromethyl)-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-ol

Prepared as previously described in Example 117 with intermediate fromExample 176 to afford(S)-1-((4-(difluoromethyl)-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-ol(2.2 mg, 7.2%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.54 (d, J=5.3Hz, 1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.84 (d, J=5.7 Hz, 1H), 7.30 (t,J=54.1 Hz, 1H), 4.04 (q, J=9.2 Hz, 2H), 2.56 (s, 3H), 1.83 (dt, J=12.8,6.4 Hz, 1H), 1.46 (d, J=5.9 Hz, 2H), 1.24 (s, 3H), 0.94 (dd, J=6.7, 1.6Hz, 6H); LCMS (ESI) m/e 351.1 [(M+H)⁺, calcd C₁₉H₂₅F₂N₂O₂, 351.2]; LC/MSretention time (method B): t_(R)=1.91 min.

Example 179 (S)-methyl(5-((2-amino-2-(fluoromethyl)-4-methylpentyl)oxy)-6-(difluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate

Part A: (E/Z)-2-((benzyloxy)imino)-3-fluoropropanoic acid

To a 250 mL round-bottomed flask was added O-benzylhydroxylamine (1.5338g, 12.45 mmol) and sodium 3-fluoro-2-oxopropanoate (1.595 g, 12.45 mmol)in ethanol (36 mL) to give a white suspension. The mixture was heated at80° C. for 15 h. The ethanol was stripped off. The off-white solid wasdissolved in EtOAc and 15 mL 1N HCl. The layer was separated. Theaqueous layer was extracted three time with EtOAc. The combined organicsolution was dried and concentrated to afford(E/Z)-2-((benzyloxy)imino)-3-fluoropropanoic acid (2.51 g, 96%) as a tansolid. LCMS indicated likely E/Z isomers (about ¼ ratio). The materialwas used as is.

Part B: 2-((benzyloxy)amino)-2-(fluoromethyl)-4-methylpent-4-enoic acid

To a 250 mL round-bottomed flask was added(E/Z)-2-((benzyloxy)imino)-3-fluoropropanoic acid (2.32 g, 10.99 mmol)and 3-bromo-2-methylpropene (4.43 mL, 43.9 mmol) in THE (10.00 mL) andaqueous NH₄Cl (50 mL) to give a tan solution. Zinc (3.59 g, 54.9 mmol)was added portionwise. The mixture was stirred at rt for 30 min. Themixture was diluted with water and EtOAc. The layers were separated. Theaqueous layer was extracted twice with EtOAc. The combined organiclayers were washed with brine, dried and concentrated to a densesemi-solid. First silica gel chromatography up to 50% EtOAc/hexane didnot purify the desired product and the 2nd silica gel chromatography upto 10% MeOH/CH₂Cl₂ (Rf˜0.3) afforded2-((benzyloxy)amino)-2-(fluoromethyl)-4-methylpent-4-enoic acid (2.33 g,76%) as a white solid: ¹H NMR (400 MHz, Chloroform-d) δ 7.44-7.31 (m,5H), 6.94 (s, 1H), 4.98 (p, J=1.6 Hz, 1H), 4.88 (d, J=2.3 Hz, 1H),4.87-4.61 (m, 4H), 2.40 (d, J=1.2 Hz, 2H), 1.77 (s, 3H); ¹⁹F NMR (376MHz, Chloroform-d) δ −233.34; LCMS (ESI) m/e 290.1 [(M+Na)⁺, calcdC₁₄H₁₈FNNaO₃, 290.1]; LC/MS retention time (method B): t_(R)=2.04 min.

The racmeic compound (2 g) was separated by chiral super critical fluidchromatography (Column: ChiralPak AD-H, 30×250 mm, 5 μm); Mobile Phase:10% EtOH/90% CO₂ to give the two enantiomers.

Analytical super critical fluid chromatography conditions: Column:ChiralPak AD-H, 4.6×250 mm, 5 μm; BPR pressure: 100 bars; Temperature:35° C.; Flow rate: 2.0 mL/min; Mobile Phase: 20% EtOH/80% CO₂; DetectorWavelength: UV 205 nm.

Enantiomer 1 (0.9 g, 90% recovery, e.e. %>99.9%, α_(D)=+7.87° (CHCl₃,3.05 mg/ml)): (S)-benzyl4-methyl-4-(2-methylallyl)-1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide HPLC retention time=3.00 min.

Enantiomer 2 (0.9 g, 90% recovery, e.e. %=92.6%, α_(D)=−9.20° (CHCl₃,3.15 mg/ml)): (R)-benzyl4-methyl-4-(2-methylallyl)-1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide HPLC retention time=3.52 min.

The absolute structures were assigned based on the comparison of theoptical rotations of the free amino alcohol below with the des-Fanalogs, and were further proved by the biology data of the finalexamples (analogs made from the S-enantiomer (1) were more potent thananalogs made from the R-enantiomer (2) as was seen with the otherexamples).

Part C: (S)-2-amino-2-(fluoromethyl)-4-methylpentanoic acid

To a 1 L round-bottomed flask was added(S)-2-((benzyloxy)amino)-2-(fluoromethyl)-4-methylpent-4-enoic acid(0.89 g, 3.33 mmol) in MeOH (30 mL) to give a colorless solution. Pd—C(0.709 g, 0.666 mmol) was added. The mixture was stirred under hydrogen(balloon) for 16 h. LCMS showed complete disappearance of startingmaterial. The mixture was filtered and rinsed with MeOH. The filteredclear solution was concentrated to afford(S)-2-amino-2-(fluoromethyl)-4-methylpentanoic acid (510 mg, 94%) as awhite solid: ¹H NMR (400 MHz, Methanol-d4) δ 4.62 (ddd, J=62.0, 47.4,10.0 Hz, 2H), 1.94-1.66 (m, 3H), 1.01 (dd, J=6.3, 3.9 Hz, 6H); ¹⁹F NMR(376 MHz, Methanol-d4) δ −229.19; α_(D)=+21.61° (MeOH, 2.85 mg/mL).

Part D: (S)-2-amino-2-(fluoromethyl)-4-methylpentan-1-ol

To a 250 mL round-bottomed flask was added(S)-2-amino-2-(fluoromethyl)-4-methylpentanoic acid (496 mg, 3.04 mmol)in tetrahydrofuran (15 mL) to give a colorless solution under nitrogen.BH₃.THF (12.16 mL, 12.16 mmol) was added under nitrogen. The mixture wasstirred at rt over the weekend for 66 h. TLC showed (10% MeOH/CH2Cl₂, I₂stain) a new peak above the baseline. The reaction was quenched withMeOH. Volatiles were removed. The residue was treated with 30 mL 1N HCland heated at 50° C. for 1 h. After cooling down, the mixture was thenbasified with 40 mL 1N NaOH and extracted three times with CH₂Cl₂. Thecombined organic solution was dried and concentrated to give(S)-2-amino-2-(fluoromethyl)-4-methylpentan-1-ol (377 mg, 83%) as acolorless oil: ¹H NMR (400 MHz, Chloroform-d) δ 4.31 (dd, J=47.7, 0.9Hz, 2H), 3.53 (dd, J=10.8, 1.3 Hz, 1H), 3.42 (dd, J=10.8, 3.0 Hz, 1H),1.79 (m, 4H), 1.44-1.32 (m, 2H), 1.00 (d, J=1.8 Hz, 3H), 0.99 (d, J=1.8Hz, 3H); ⁹F NMR (376 MHz, Chloroform-d) δ −227.90; α_(D)=−1.00° (CHCl₃,2.40 mg/mL).

Part E:(S)-1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine

To a 2 mL pressure bottle was added(S)-2-amino-2-(fluoromethyl)-4-methylpentan-1-ol (65.7 mg, 0.440 mmol)and 6-bromo-2-(difluoromethyl)-3-fluoropyridine (100 mg, 0.440 mmol) intetrahydrofuran (0.6 mL) to give a colorless solution. Potassiumtert-butoxide (0.528 mL, 0.528 mmol) (1.0 M in THF) was added undernitrogen. The bottle was sealed and the mixture was stirred at 70° C.for 16 h. The mixture was partitioned between water and EtOAc. Thelayers were separated. The aqueous layer was extracted with EtOAc. Thecombined organic solution was washed with brine, dried and concentratedto a tan oil (140 mg, 90%): ¹H NMR (400 MHz, Chloroform-d) δ 7.56 (dt,J=8.7, 1.0 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 6.68 (t, J=53.8 Hz, 1H),4.50-4.25 (m, 2H), 3.93 (ddd, J=32.5, 8.5, 1.8 Hz, 2H), 1.87 (dq,J=12.7, 6.3 Hz, 1H), 1.52-1.44 (m, 2H), 1.03 (d, J=6.7 Hz, 3H), 1.00 (d,J=6.7 Hz, 3H); ¹⁹F NMR (376 MHz, Chloroform-d) δ −117.34, −225.58; LCMS(ESI) m/e 355.1 [(M+H)⁺, calcd C₁₃H₉BrF₃N₂O, 355.1]; LC/MS retentiontime (method B): t_(R)=1.69 min.

Part F.(S)-methyl(5-((2-amino-2-(fluoromethyl)-4-methylpentyl)oxy)-6-(difluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate

Prepared as previously described for Example 117 but at 80° C. for 5 hto afford the titled product (9.7 mg, 36%): ¹H NMR (500 MHz, DMSO-d₆) δ8.50 (s, 1H), 8.36 (d, J=5.2 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.83 (d,J=8.8 Hz, 1H), 7.67 (d, J=5.3 Hz, 1H), 7.23 (t, J=53.5 Hz, 1H), 4.33(dq, J=47.8, 8.9 Hz, 2H), 4.07-3.92 (m, 2H), 3.71 (s, 3H), 1.89 (dd,J=12.7, 6.5 Hz, 1H), 1.50-1.31 (m, 2H), 0.96 (d, J=6.6 Hz, 3H), 0.93 (d,J=6.6 Hz, 3H); LCMS (ESI) m/e 427.3 [(M+H)⁺, calcd C₂₀H₂₆F₃N₄O₃, 427.2];LC/MS retention time (method B): t_(R)=1.66 min.

Example 180 (R)-methyl(5-((2-amino-2-(fluoromethyl)-4-methylpentyl)oxy)-6-(difluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate

Part A: (R)-2-amino-2-(fluoromethyl)-4-methylpentanoic acid

Prepared as previously described in Example 179, Part C to afford(R)-2-amino-2-(fluoromethyl)-4-methylpentanoic acid (512 mg, 94%) as awhite solid: ¹H NMR (400 MHz, Methanol-d₄) δ 4.62 (ddd, J=62.0, 47.4,10.0 Hz, 2H), 1.94-1.66 (m, 3H), 1.01 (dd, J=6.3, 3.9 Hz, 6H); ¹⁹F NMR(376 MHz, Methanol-d4) δ −229.19; α_(D)=−20.29° (MeOH, 2.70 mg/mL).

Part B: (R)-2-amino-2-(fluoromethyl)-4-methylpentan-1-ol

Prepared as previously described in Example 179, Part D to afford(R)-2-amino-2-(fluoromethyl)-4-methylpentan-1-ol (362 mg, 80%) as acolorless oil: ¹H NMR (400 MHz, Methanol-d₄) δ 4.31 (d, J=47.7 Hz, 2H),3.53 (dd, J=10.8, 1.3 Hz, 1H), 3.42 (dd, J=10.8, 3.0 Hz, 1H), 1.79 (tt,J=12.8, 6.4 Hz, 4H), 1.38 (td, J=5.6, 1.8 Hz, 2H), 1.00 (d, J=1.8 Hz,3H), 0.99 (d, J=1.9 Hz, 3H); ¹⁹F NMR (376 MHz, Chloroform-d) δ −227.87;α_(D)=+1.110 (CHCl₃, 2.70 mg/mL).

Part C:(R)-1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine

Prepared as previously described in Example 179, Part E to afford(R)-1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine(145 mg, 96%) as a colorless oil: ¹H NMR (400 MHz, Methanol-d₄) δ 7.56(dt, J=8.6, 1.0 Hz, 1H), 7.26 (d, J=8.7 Hz, 1H), 6.69 (t, J=53.8 Hz,1H), 4.49-4.26 (m, 2H), 3.93 (ddd, J=32.8, 8.6, 1.8 Hz, 2H), 1.88 (dp,J=12.8, 6.4 Hz, 1H), 1.56-1.41 (m, 4H), 1.03 (d, J=6.6 Hz, 3H), 1.00 (d,J=6.6 Hz, 3H); ¹⁹F NMR (376 MHz, Chloroform-d) δ −117.50, −225.55; LCMS(ESI) m/e 355.1 [(M+H)⁺, calcd C₁₃H₉BrF₃N₂O, 355.1]; LC/MS retentiontime (method B): t_(R)=1.68 min.

Part D: (R)-methyl(5-((2-amino-2-(fluoromethyl)-4-methylpentyl)oxy)-6-(difluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate

Prepared as previously described In Example 179 to afford (R)-methyl(5-((2-amino-2-(fluoromethyl)-4-methylpentyl)oxy)-6-(difluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate(8.8 mg, 33%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.50 (s, 1H), 8.36 (d, J=5.4Hz, 1H), 8.18 (d, J=8.7 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.67 (d, J=5.2Hz, 1H), 7.23 (t, J=53.5 Hz, 1H), 4.33 (dq, J=47.7, 9.0 Hz, 2H),4.11-3.93 (m, 2H), 3.71 (s, 3H), 1.89 (p, J=6.4 Hz, 1H), 1.50-1.32 (m,2H), 0.96 (d, J=6.7 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H); LCMS (ESI) m/e427.3 [(M+H)⁺, calcd C₂H₂₆F₃N₄O₃, 427.2]; LC/MS retention time (methodB): t_(R)=1.62 min.

Example 181 (S)-methyl(5-((2-amino-2-(fluoromethyl)-4-methylpentyl)oxy)-4-(difluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate

Part A:(S)-1-((6-bromo-4-(difluoromethyl)pyridin-3-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine

Prepared as previously described in Example 19 to afford(S)-1-((6-bromo-4-(difluoromethyl)pyridin-3-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine(157 mg, 98%) as a tan oil: ¹H NMR (400 MHz, Methanol-d₄) δ 8.16 (s,1H), 7.62 (s, 1H), 6.80 (t, J=54.4 Hz, 1H), 4.35 (ddd, J=47.4, 36.8, 9.0Hz, 2H), 4.01 (qd, J=8.7, 1.7 Hz, 2H), 1.87 (dp, J=12.9, 6.4 Hz, 1H),1.48-1.43 (m, 2H), 1.03 (d, J=6.6 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H); ¹⁹FNMR (376 MHz, Chloroform-d) δ −119.66, −226.04; LCMS (ESI) m/e 355.1[(M+H)⁺, calcd C₁₃H₁₉BrF₃N₂O, 355.1]; LC/MS retention time (method B):t_(R)=1.78 min.

Part B: (S)-methyl(5-((2-amino-2-(fluoromethyl)-4-methylpentyl)oxy)-4-(difluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate

Prepared as previously described for Example 179 to afford the titledproduct (4.0 mg, 17%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.73 (s, 1H), 8.53(s, 1H), 8.36 (d, J=5.2 Hz, 1H), 8.08 (s, 1H), 7.70 (d, J=5.3 Hz, 1H),7.35 (t, J=53.9 Hz, 1H), 4.45-4.23 (m, 2H), 4.20-4.05 (m, 2H), 3.71 (s,3H), 1.90 (p, J=6.5 Hz, 1H), 1.40 (qd, J=13.9, 5.7 Hz, 2H), 0.96 (d,J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H); LCMS (ESI) m/e 427.3 [(M+H)⁺,calcd C₂H₂₆F₃N₄O₃, 427.2]; LC/MS retention time (method B): t_(R)=1.67min.

Example 182 (R)-methyl(5-((2-amino-2-(fluoromethyl)-4-methylpentyl)oxy)-4-(difluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate

Part A:(R)-1-((6-bromo-4-(difluoromethyl)pyridin-3-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine

Prepared as previously described in Example 19 to afford(R)-1-((6-bromo-4-(difluoromethyl)pyridin-3-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine(163 mg, 100%) as a tan oil: ¹H NMR (400 MHz, Methanol-d₄) δ 8.17 (s,1H), 7.62 (s, 1H), 6.80 (t, J=54.4 Hz, 1H), 4.35 (ddd, J=47.5, 36.9, 9.0Hz, 2H), 4.01 (qd, J=8.7, 1.7 Hz, 2H), 1.87 (dp, J=12.8, 6.4 Hz, 1H),1.54-1.43 (m, 4H), 1.03 (d, J=6.6 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H); ¹⁹FNMR (376 MHz, Chloroform-d) δ −119.62, −226.06; LCMS (ESI) m/e 355.1[(M+H)⁺, calcd C₁₃H₉BrF₃N₂O, 355.1]; LC/MS retention time (method B):t_(R)=1.79 min.

Part B: (R)-methyl(5-((2-amino-2-(fluoromethyl)-4-methylpentyl)oxy)-4-(difluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate

Prepared as previously described for Example 179 to afford (R)-methyl(5-((2-amino-2-(fluoromethyl)-4-methylpentyl)oxy)-4-(difluoromethyl)-[2,4′-bipyridin]-2′-yl)carbamate(3.4 mg, 13%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.73 (s, 1H), 8.53 (s, 1H),8.36 (d, J=5.2 Hz, 1H), 8.08 (s, 1H), 7.70 (d, J=5.3 Hz, 1H), 7.35 (t,J=53.9 Hz, 1H), 4.43-4.24 (m, 2H), 4.20-4.04 (m, 2H), 3.71 (s, 3H), 1.90(dt, J=12.6, 6.2 Hz, 1H), 1.40 (qd, J=14.4, 5.7 Hz, 2H), 0.96 (d, J=6.6Hz, 3H), 0.94 (d, J=6.7 Hz, 3H); LCMS (ESI) m/e 427.3 [(M+H)⁺, calcdC₂H₂₆F₃N₄O₃, 427.2]; LC/MS retention time (method B): t_(R)=1.65 min.

Example 183(S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine

Prepared as previously described for Example 179 but for 3 h to afford(S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine(10 mg, 28%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.80 (d, J=5.1 Hz, 1H), 8.41(d, J=8.8 Hz, 1H), 8.33 (s, 1H), 8.22 (d, J=5.2 Hz, 1H), 7.88 (d, J=8.9Hz, 1H), 7.39-7.14 (m, 1H), 7.00 (d, J=54.8 Hz, 1H), 4.43-4.23 (m, 2H),4.10-3.96 (m, 2H), 1.90 (dt, J=12.8, 6.4 Hz, 1H), 1.49-1.32 (m, 2H),0.96 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.5 Hz, 3H); LCMS (ESI) m/e 404.3[(M+H)⁺, calcd C₁₉H₂₃F₅N₃O, 404.2]; LC/MS retention time (method B):t_(R)=1.90 min.

Example 184(S)-1-((2′,4-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine

Prepared as previously described for Example 179 but for 3 h to afford(S)-1-((2′,4-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine(15.1 mg, 45%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.79 (d, J=5.3 Hz, 1H), 8.76(s, 1H), 8.37 (s, 1H), 8.33 (s, 1H), 8.26 (d, J=5.2 Hz, 1H), 7.35 (t,J=53.8 Hz, 1H), 7.05 (t, J=54.9 Hz, 1H), 4.43-4.25 (m, 2H), 4.21-4.04(m, 2H), 1.90 (dt, J=12.8, 6.4 Hz, 1H), 1.48-1.33 (m, 2H), 0.96 (d,J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H); LCMS (ESI) m/e 404.3 [(M+H)⁺,calcd C₁₉H₂₃F₅N₃O, 404.2]; LC/MS retention time (method B): t_(R)=1.86min.

Example 185(R)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine

Prepared as previously described for Example 179 but for 3 h to afford(R)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine(10 mg, 28%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.80 (d, J=5.1 Hz, 1H), 8.41(d, J=8.8 Hz, 1H), 8.33 (s, 1H), 8.22 (d, J=5.2 Hz, 1H), 7.87 (d, J=8.8Hz, 1H), 7.40-7.15 (m, 1H), 6.99 (d, J=54.9 Hz, 1H), 4.44-4.23 (m, 2H),4.11-3.95 (m, 2H), 1.90 (dt, J=12.7, 6.3 Hz, 1H), 1.49-1.32 (m, 2H),0.96 (d, J=6.7 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H); LCMS (ESI) m/e 404.3[(M+H)⁺, calcd C₁₉H₂₃F₅N₃O, 404.2]; LC/MS retention time (method B):t_(R)=1.87 min.

Example 186(R)-1-((2′,4-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine

Prepared as previously described for Example 179 to afford(R)-1-((2′,4-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine(7.7 mg, 16%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.79 (d, J=5.1 Hz, 1H), 8.76(s, 1H), 8.37 (s, 1H), 8.33 (s, 1H), 8.26 (d, J=5.3 Hz, 1H), 7.35 (t,J=53.8 Hz, 1H), 7.05 (t, J=54.8 Hz, 1H), 4.45-4.24 (m, 2H), 4.21-4.03(m, 2H), 1.90 (p, J=6.4 Hz, 1H), 1.50-1.33 (m, 2H), 0.97 (d, J=6.6 Hz,3H), 0.94 (d, J=6.6 Hz, 3H); LCMS (ESI) m/e 404.3 [(M+H)⁺, calcdC₁₉H₂₃F₅N₃O, 404.2]; LC/MS retention time (method B): t_(R)=1.87 min.

Example 187(S)-1-((4-(difluoromethyl)-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine

Prepared as previously described for Example 179 to afford(S)-1-((4-(difluoromethyl)-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine(16.8 mg, 50%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.71 (s, 1H), 8.54 (d, J=5.4Hz, 1H), 8.19 (s, 1H), 7.94 (s, 1H), 7.84 (d, J=5.2 Hz, 1H), 7.34 (t,J=53.9 Hz, 1H), 4.42-4.25 (m, 2H), 4.18-4.03 (m, 2H), 2.56 (s, 3H), 1.90(dt, J=13.1, 6.5 Hz, 1H), 1.40 (qd, J=14.3, 5.7 Hz, 2H), 0.96 (d, J=6.6Hz, 3H), 0.94 (d, J=6.7 Hz, 3H); LCMS (ESI) m/e 368.3 [(M+H)⁺, calcdC₁₉H₂₅F₃N₃O, 368.2]; LC/MS retention time (method B): t_(R)=1.39 min.

Example 188(R)-1-((4-(difluoromethyl)-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine

Prepared as previously described for Example 179 to afford(R)-1-((4-(difluoromethyl)-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine(20.5 mg, 59%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.71 (s, 1H), 8.54 (d, J=5.4Hz, 1H), 8.19 (s, 1H), 7.94 (s, 1H), 7.84 (d, J=5.2 Hz, 1H), 7.34 (t,J=53.9 Hz, 1H), 4.44-4.24 (m, 2H), 4.18-4.02 (m, 2H), 2.56 (s, 3H), 1.90(dt, J=12.9, 6.3 Hz, 1H), 1.40 (qd, J=14.2, 5.8 Hz, 2H), 0.96 (d, J=6.6Hz, 3H), 0.94 (d, J=6.7 Hz, 3H); LCMS (ESI) m/e 368.3 [(M+H)⁺, calcdC₁₉H₂₅F₃N₃O, 368.2]; LC/MS retention time (method B): t_(R)=1.47 min.

Example 189(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)acetamide

Part A:(S)-tert-butyl(1-((3-chloro-5-(5,7-difluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Prepared as described in Example 77. Obtained (S)-tert-butyl(1-((3-chloro-5-(5,7-difluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(33.4 mg, 48%). LCMS (ESI) m/e 506.0 [(M+H)⁺, calcd C₂₆H₃₁F₂N₃Cl₁O₃,506.2]; LC/MS retention time (method B): t_(R)=2.48 min.

Part B:(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)acetamide

TFA deprotection was carried out as described in Example 32. Obtained(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)acetamide(27 mg, 100%) as a colorless solid. ¹H NMR (500 MHz, DMSO-d₆) δ 10.53(s, 1H), 8.33 (d, J=4.9 Hz, 2H), 7.61 (dd, J=12.5, 2.2 Hz, 1H), 7.52(dd, J=8.5, 2.2 Hz, 1H), 7.43-7.37 (m, 1H), 7.32 (t, J=8.7 Hz, 1H), 3.97(dd, J=9.5, 4.9 Hz, 1H), 3.90 (dd, J=9.5, 6.5 Hz, 1H), 3.12 (dt, J=11.9,5.4 Hz, 1H), 2.12 (s, 3H), 1.81 (dq, J=13.0, 6.5 Hz, 1H), 1.33 (ddd,J=13.5, 8.5, 5.0 Hz, 1H), 1.26 (ddd, J=13.5, 8.5, 5.5 Hz, 1H), 0.92 (d,J=6.6 Hz, 3H), 0.88 (d, J=6.5 Hz, 3H); LCMS (ESI) m/e 406.0 [(M+H)⁺,calcd C₂₁H₂₃F₂N₃Cl₁O₁, 406.1]; LC/MS retention time (method B):t_(R)=2.03 min.

Example 190(S)-1-((3-chloro-5-(7-fluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((3-chloro-5-(7-fluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Intermediate7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline wasprepared as described in Example 77, Part C. Suzuki coupling wasperformed as described in Example 77, Part D. Obtained (S)-tert-butyl(1-((3-chloro-5-(7-fluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(10.6 mg, 76% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.97 (d, J=4.3Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.91-7.80 (m, 3H), 7.37 (ddd, J=9.3,8.0, 2.5 Hz, 1H), 7.30 (d, J=4.0 Hz, 1H), 4.63 (d, J=10.5 Hz, 1H), 4.47(d, J=10.5 Hz, 1H), 1.93-1.83 (m, 2H), 1.68 (d, J=8.8 Hz, 1H), 1.46 (s,3H), 1.44 (s, 9H), 1.02 (m, 6H). ¹⁹F NMR (376 MHz, CHLOROFORM-d) δ−109.18 (s, 1F). LCMS (ESI) m/e 488.0 [(M+H)⁺, calcd C₂₆H₃₂F₁N₃Cl₁O₃,488.2]; LC/MS retention time (method B): t_(R)=2.39 min.

Part B:(S)-1-((3-chloro-5-(7-fluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

TFA deprotection was performed as described in Example 32. Obtained(S)-1-((3-chloro-5-(7-fluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(4.4 mg, 50% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 9.06-8.97 (m, 1H),8.38-8.29 (m, 1H), 8.25-8.16 (m, 1H), 8.04-7.83 (m, 2H), 7.65-7.51 (m,2H), 4.27-4.13 (m, 2H), 1.95-1.79 (m, 1H), 1.56-1.40 (m, 2H), 1.26-1.16(m, 3H), 1.03-0.91 (m, 6H). LCMS (ESI) me 409.9 [(M+Na), calcdC₂H₂₃F₁N₃Cl₁O₁Na₁, 410.1]; LC/MS retention time (method B): t_(R)=1.85min.

Example 191(S)-1-((3-chloro-5-(6-fluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 191 to afford(S)-1-((3-chloro-5-(6-fluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(9.4 mg, 0.024 mmol, 50% yield for the final step) as a colorless solid.¹H NMR (600 MHz, DMSO-d₆) δ 9.06-8.97 (m, 1H), 8.38-8.29 (m, 1H),8.25-8.16 (m, 1H), 8.04-7.83 (m, 2H), 7.65-7.51 (m, 2H), 4.27-4.13 (m,2H), 1.95-1.79 (m, 1H), 1.56-1.40 (m, 2H), 1.26-1.16 (m, 3H), 1.03-0.91(m, 6H), two exchangeable protons not observed; LCMS (ESI) m/e 388.1[(M+H)⁺, calcd C₂₁H₂₄FN₃ClO, 388.2]; LC/MS retention time (method E):t_(R)=1.82 min.

Example 192(S)-1-((3-chloro-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((3-chloro-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Intermediate (S)-tert-butyl(1-((3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamatewas prepared as described in Example 77, Part C. Suzuki coupling wasperformed as described in Example 77, Part D. (Crude was carried on nextstep). LCMS (ESI) m/e 457.1 [(M+Na)⁺, calcd C₂₃H₃₁N₄ClO₃Na, 457.2];LC/MS retention time (method B): t_(R)=2.41 min.

Part B:(S)-1-((3-chloro-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

TFA deprotection was performed as described in Example 32 to obtain(S)-1-((3-chloro-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine10.1 mg, 0.030 mmol, 51% yield in two steps). ¹H NMR (500 MHz, DMSO-d₆)δ 8.94 (d, J=2.2 Hz, 1H), 8.76 (d, J=5.5 Hz, 1H), 8.63 (d, J=1.8 Hz,1H), 7.95 (d, J=5.5 Hz, 1H), 4.22-4.14 (m, 2H), 2.68 (s, 3H), 1.85-1.78(m, 1H), 1.42 (dd, J=9.0, 5.3 Hz, 2H), 1.15 (s, 3H), 0.92 (m, 6H); LCMS(ESI) m/e 318.1 [(M-NH₂)+, calcd C₁₇H₂N₃C10, 318.1]; LC/MS retentiontime (method B): t_(R)=1.83 min.

Example 193(S)-1-((2′-chloro-5-(difluoromethyl)-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: 5-Bromo-3-(difluoromethyl)-2-fluoropyridine

To a solution of 5-bromo-2-fluoronicotinaldehyde (0.8212 g, 4.03 mmol)in CH₂Cl₂ (15 mL) at 0° C. was added DAST (1.064 mL, 8.05 mmol). Thereaction was stirred at 0° C. for 1 h then warmed to room temperature.The stirring was continued for 3 h. The reaction was poured into an icecold 1N NaOH solution. The organic layer was separated and the aqueouslayer was extracted DCM (2×). The DCM layers were combined, dried(Na₂SO₄), filtered and concentrated under reduced pressure to give crude5-bromo-3-(difluoromethyl)-2-fluoropyridine (0.81 g, 3.58 mmol, 89%yield) as a brown solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.43-8.38 (m,1H), 8.18-8.13 (m, 1H), 6.82 (t, J=52.0 Hz, 1H); ¹⁹F NMR (376 MHz,CHLOROFORM-d) δ −74.33 (br. s., 1F), −115.87 (s, 2F); LCMS (ESI) m/e205.9 [(M-F)⁺, calcd C₆H₃BrNF₂, 205.9]; LC/MS retention time (method B):t_(R)=1.88 min.

Part B:(S)-1-((5-bromo-3-(difluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

To (S)-2-amino-2,4-dimethylpentan-1-ol (0.3359 g, 2.56 mmol) and5-bromo-3-(difluoromethyl)-2-fluoropyridine (0.579 g, 2.56 mmol) in THE(5 mL) at room temperature was added potassium tert-butoxide (3.07 mL,3.07 mmol). The reaction was stirred at room temperature overnight. Thereaction was quenched by addition of water and the crude solution wasdiluted with ethyl acetate. The ethyl acetate layer was separated andwashed with water (3×), dried (Na₂SO₄), filtered and concentrated underreduced pressure. The product was purified by silica gel chromatography(eluted with 0-10% methanol in CH₂Cl₂) to obtain(S)-1-((5-bromo-3-(difluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(0.63 g, 0.923 mmol, 73% yield) as a yellow liquid. ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.31-8.27 (m, 1H), 7.96-7.93 (m, 1H), 6.97-6.64 (m, 1H),4.15 (s, 2H), 1.85-1.74 (m, 1H), 1.45 (t, J=5.8 Hz, 2H), 1.20 (s, 3H),0.98 (m, 6H). ¹⁹F NMR (376 MHz, CHLOROFORM-d) δ −117.61 (s, 2F); LCMS(ESI) m/e 320.1 [(M-NH₂)+, calcd C₁₃H₁₇BrNF₂O, 320.1]; LC/MS retentiontime (method B): t_(R)=1.99 min.

Part C:(S)-1-((2′-chloro-5-(difluoromethyl)-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine

A mixture of 2N sodium carbonate solution (0.050 ml, 0.099 mmol),1,1′-bis(diphenylphosphine)ferrocene-palladium(II)dichloridedichoromethane complex (2.022 mg, 2.476 μmol),2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.018g, 0.074 mmol) and(S)-1-((5-bromo-3-(difluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(0.0167 g, 0.050 mmol) in dioxane (0.8 mL) (degassed) was heated at 80°C. for 2 h. The reaction was filtered through celite and purified byreverse phase Prep HPLC. Obtained(S)-1-((2′-chloro-5-(difluoromethyl)-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine(13.1 mg, 0.035 mmol, 72% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.83 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 8.43 (s, 1H), 7.98 (s,1H), 7.84 (d, J=4.8 Hz, 1H), 7.27 (t, J=55.0 Hz, 1H), 4.22-4.14 (m, 2H),1.83-1.73 (m, 1H), 1.48-1.37 (m, 2H), 1.15 (s, 3H), 0.91 (m, 6H). LCMS(ESI) m/e 353.1 [(M-NH₂), calcd C₁₈H₂₀N₂ClF₂O, 353.1]; LC/MS retentiontime (method B): t_(R)=1.96 min.

Example 194(S)-1-((5-(difluoromethyl)-2′-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 193 to afford(S)-1-((5-(difluoromethyl)-2′-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine(9.2 mg, 0.026 mmol, 45% yield for the final step) as a colorless solid.¹H NMR (500 MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.50 (d, J=5.2 Hz, 1H), 8.33(s, 1H), 7.66 (s, 1H), 7.57 (d, J=4.9 Hz, 1H), 7.45-7.11 (m, 1H),4.24-4.11 (m, 2H), 2.53 (s, 3H), 1.82-1.72 (m, 1H), 1.44 (qd, J=13.9,5.5 Hz, 2H), 1.16 (s, 3H), 0.92 (d, J=6.7 Hz, 3H), 0.89 (d, J=6.4 Hz,3H) two exchangeable protons not observed; LCMS (ESI) m/e 350.0 [(M+H)⁺,calcd C₁₉H₂₆F₂N₃O, 350.2]; LC/MS retention time (method E): t_(R)=2.62min.

Example 195(S)-1-((3-(difluoromethyl)-5-(7-fluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Part A:(S)-1-((3-(difluoromethyl)-5-(7-fluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Intermediate7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline wasprepared as described in Example 77, Part C. Final product was preparedas described in Example 193 to obtain(S)-1-((3-(difluoromethyl)-5-(7-fluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(13.9 mg, 0.034 mmol, 34% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.00 (d,J=4.4 Hz, 1H), 8.51 (s, 1H), 8.15 (s, 1H), 7.97-7.85 (m, 2H), 7.59 (td,J=8.8, 2.6 Hz, 1H), 7.56 (d, J=4.4 Hz, 1H), 7.28 (t, J=55.0 Hz, 1H),4.18 (s, 2H), 1.86-1.76 (m, 1H), 1.48-1.36 (m, 2H), 1.15 (s, 3H), 0.94(m, 6H); LCMS (ESI) m/e 387.1 [(M-NH₂)+, calcd C₂₂H₂₂N₂F₃O, 387.2];LC/MS retention time (method B): t_(R)=1.86 min.

Example 196(S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-(difluoromethyl)-[3,4′-bipyridin]-2′-yl)carbamate

Prepared as described in Example 193. Obtained (S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-(difluoromethyl)-[3,4′-bipyridin]-2′-yl)carbamate(8.0 mg, 0.018 mmol, 40% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.56(br. s., 1H), 8.34 (d, J=4.8 Hz, 1H), 8.24 (br. s., 1H), 8.13 (br. s.,2H), 7.19 (d, J=3.8 Hz, 1H), 7.11-6.73 (m, 1H), 4.26 (br. s., 2H), 3.85(s, 3H), 1.77 (m 1H), 1.50 (br. s., 2H), 1.25 (br. s., 3H), 1.00 (t,J=7.4 Hz, 6H), two exchangeable protons not observed; LCMS (ESI) m/e431.1 [(M+Na)⁺, calcd C₂₀H₂₆N₄F₂O₃Na, 431.2]; LC/MS retention time(method B): t_(R)=1.78 min.

Example 197(S)-1-((5-(7-chloroquinolin-4-yl)-3-(difluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Intermediate(5)-1-((3-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-aminewas prepared as described in Example 77, Part C. Intermediate4-bromo-7-chloroquinoline was prepared as described in Example 77, PartB. Suzuki reaction was performed as described in Example 193. Obtained(S)-1-((5-(7-chloroquinolin-4-yl)-3-(difluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(7.8 mg, 0.019 mmol, 34% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.02 (d,J=4.6 Hz, 1H), 8.53 (s, 1H), 8.20 (d, J=1.8 Hz, 1H), 8.16 (s, 1H), 7.88(d, J=9.2 Hz, 1H), 7.69 (dd, J=9.0, 2.0 Hz, 1H), 7.61 (d, J=4.3 Hz, 1H),7.29 (t, J=55.0 Hz, 1H), 4.22-4.16 (m, 2H), 1.83 (dt, J=12.5, 6.3 Hz,1H), 1.49-1.38 (m, 2H), 1.17 (s, 3H), 0.97-0.92 (m, 6H), twoexchangeable protons not observed; LCMS (ESI) m/e 442.0 [(M+Na)⁺, calcdC₂₂H₂₄ClN₃F₂ONa, 442.2]; LC/MS retention time (method B): t_(R)=2.09min.

Example 198(S)-1-((3-(difluoromethyl)-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Intermediate(5)-1-((3-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-aminewas prepared as described in Example 77, Part C. Suzuki reaction wasperformed as described in Example 193. Obtained(S)-1-((3-(difluoromethyl)-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(7.7 mg, 0.036 mmol, 37% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.13 (s,1H), 8.78 (d, J=5.2 Hz, 1H), 8.69 (s, 1H), 7.99 (d, J=5.2 Hz, 1H), 7.29(t, J=55.0 Hz, 1H), 4.19 (d, J=1.8 Hz, 2H), 2.70 (s, 3H), 1.85-1.76 (m,1H), 1.46-1.36 (m, 2H), 1.14 (s, 3H), 0.92 (m, 6H); LCMS (ESI) m/e 334.1[(M-NH₂)+, calcd C₁₈H₂₂N₃F₂O, 334.2]; LC/MS retention time (method B):t_(R)=1.91 min.

Example 199(S)-1-((2′,5-bis(difluoromethyl)-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine

Intermediate(S)-1-((3-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-aminewas prepared as described in Example 77, Part C. Suzuki reaction wasperformed as described in Example 193. Obtained(S)-1-((2′,5-bis(difluoromethyl)-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine(9.2 mg, 0.023 mmol, 39% yield). ¹H NMR (500 MHz, DMSO-d6) δ 8.86 (s,1H), 8.77 (d, J=5.2 Hz, 1H), 8.45 (s, 1H), 8.10 (s, 1H), 8.00 (d, J=4.6Hz, 1H), 7.26 (t, J=55.0 Hz, 1H), 7.02 (t, J=55.0 Hz, 1H), 4.18 (d,J=1.8 Hz, 2H), 1.85-1.75 (m, 1H), 1.48-1.36 (m, 2H), 1.15 (s, 3H), 0.94(d, J=6.7 Hz, 3H), 0.92 (d, J=6.7 Hz, 3H), two exchangeable protons notobserved; LCMS (ESI) m/e 369.1 [(M-NH₂)+, calcd C₁₉H₂N₂F₄O, 369.2];LC/MS retention time (method B): t_(R)=1.91 min.

Example 200(S)-1-((3-(difluoromethyl)-5-(6-fluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Intermediate6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline wasprepared as described in Example 77, Part B and C. Suzuki reaction wasperformed as described in Example 193. Obtained(S)-1-((3-(difluoromethyl)-5-(6-fluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(27.2 mg, 0.067 mmol, 39% yield). ¹H NMR (500 MHz, DMSO-d6) δ 8.97 (d,J=4.4 Hz, 1H), 8.52 (s, 1H), 8.22 (dd, J=9.2, 5.9 Hz, 1H), 8.16 (s, 1H),7.81-7.72 (m, 1H), 7.61 (d, J=4.4 Hz, 1H), 7.51 (dd, J=10.1, 2.8 Hz,1H), 7.28 (t, J=55.0 Hz, 1H), 4.19 (s, 2H), 1.86-1.77 (m, 1H), 1.49-1.37(m, 2H), 1.16 (s, 3H), 0.94 (m, 6H), two exchangeable protons notobserved; LCMS (ESI) m/e 426.2 [(M+Na)⁺, calcd C₂₂H₂₄N₃F₃ONa, 426.2];LC/MS retention time (method B): t_(R)=1.93 min.

Example 201(S)-1-((3-(difluoromethyl)-5-(5,7-difluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Intermediate(S)-tert-butyl(1-((3-chloro-5-(5,7-difluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamatewas prepared in Example 189. Suzuki reaction was performed as describedin Example 193. Obtained(S)-1-((3-(difluoromethyl)-5-(5,7-difluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(13.0 mg, 0.031 mmol, 37% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.02 (d,J=4.4 Hz, 1H), 8.43 (s, 1H), 8.10 (br. s., 1H), 7.80 (d, J=8.4 Hz, 1H),7.63-7.55 (m, 1H), 7.51 (d, J=4.4 Hz, 1H), 7.25 (t, J=55.0 Hz, 1H), 4.16(s, 2H), 1.81 (dt, J=12.5, 6.2 Hz, 1H), 1.41 (t, J=6.4 Hz, 2H), 1.14 (s,3H), 0.93 (m, 6H), two exchangeable protons not observed; LCMS (ESI) m/e405.7 [(M-NH₂)+, calcd C₂₂H₂N₂F₄O, 405.2]; LC/MS retention time (methodB): t_(R)=2.02 min.

Example 202(S)-1-((3-(difluoromethyl)-5-(7-(trifluoromethyl)quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Intermediate4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-(trifluoromethyl)quinolinewas prepared as described in Example 77, Part C. Suzuki reaction wasperformed as described in Example 193. Obtained(S)-1-((3-(difluoromethyl)-5-(7-(trifluoromethyl)quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(25.3 mg, 0.055 mmol, 37% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.14 (d,J=4.4 Hz, 1H), 8.56 (s, 1H), 8.48 (s, 1H), 8.20 (s, 1H), 8.08 (d, J=8.8Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.75 (d, J=4.4 Hz, 1H), 7.29 (t, J=55.0Hz, 1H), 4.20 (s, 2H), 1.87-1.79 (m, 1H), 1.49-1.38 (m, 2H), 1.16 (s,3H), 0.95 (m, 6H), two exchangeable protons not observed; LCMS (ESI) m/e437.1 [(M-NH₂), calcd C₂₃H₂₂N₂F₅O, 437.2]; LC/MS retention time (methodB): t_(R)=2.13 min.

Example 203(S)-1-((5-(difluoromethyl)-2′,3′-dimethyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine

Intermediate2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine wasprepared as described in Example 77, Part C. Suzuki reaction wasperformed as described in Example 193. Obtained(S)-1-((5-(difluoromethyl)-2′,3′-dimethyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine(20.4 mg, 0.056 mmol, 26% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.32 (d,J=4.0 Hz, 2H), 7.95 (s, 1H), 7.38-7.11 (m, 2H), 4.15 (s, 2H), 2.52 (br.s., 3H), 2.17 (s, 3H), 1.84-1.75 (m, 1H), 1.42 (dd, J=10.5, 5.3 Hz, 2H),1.15 (s, 3H), 0.93 (m, 6H), two exchangeable protons not observed; LCMS(ESI) m/e 347.1 [(M-NH₂)+, calcd C₂₀H₂₅N₂F₂O, 347.2]; LC/MS retentiontime (method B): t_(R)=1.48 min.

Example 204(S)-1-((3-(difluoromethyl)-5-(quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Suzuki reaction was performed as described in Example 193. Obtained(S)-1-((3-(difluoromethyl)-5-(quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(17.4 mg, 0.045 mmol 66% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.05 (d,J=4.0 Hz, 1H), 8.57 (br. s., 1H), 8.34 (br. s., 2H), 8.21 (br. s., 1H),8.18 (d, J=8.5 Hz, 1H), 7.89 (t, J=7.5 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H),7.70 (t, J=7.5 Hz, 1H), 7.65 (d, J=4.3 Hz, 1H), 7.63-7.40 (m, 1H),4.64-4.39 (m, 2H), 1.89-1.73 (m, 2H), 1.65 (dd, J=13.7, 4.6 Hz, 1H),1.42 (s, 3H), 0.97 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.1 Hz, 3H); LCMS (ESI)m/e 386.1 [(M+H)⁺, calcd C₂₂H₂₆N₃F₂O, 386.2]; LC/MS retention time(method B): t_(R)=1.68 min.

Example 205(S)-1-((3-(difluoromethyl)-5-(7-methylquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

A mixture of 2N sodium carbonate solution (0.146 mL, 0.291 mmol),(5)-1-((5-(7-chloroquinolin-4-yl)-3-(difluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(0.0611 g, 0.146 mmol) (Example197),2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.018 g, 0.146 mmol)and 1,1′-bis(diphenylphosphine)ferrocene-palladium(II)dichloridedichoromethane complex (5.94 mg, 7.28 μmol) in dioxane (1 mL) (degassed)was heated at 110° C. for 3 h. The reaction was diluted with ethylacetate and washed with water three times. The ethyl acetate layer wasseparated, dried (Na₂SO₄), filtered and concentrated under reducedpressure. The product was purified by reverse phase Prep HPLC to afford(S)-1-((3-(difluoromethyl)-5-(7-methylquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(1.1 mg, 2.5 □mol, 2% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.93 (d, J=4.4Hz, 1H), 8.51 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.73 (d, J=8.8 Hz,1H), 7.53-7.47 (m, 2H), 7.32 (t, J=55.0 Hz, 1H), 2.56 (s, 3H), 1.87-1.79(m, 1H), 1.54-1.41 (m, 2H), 1.20 (s, 3H), 0.95 (m, 6H). (NMR watersuppression also suppressed OCH₂ ether signal); LCMS (ESI) m/e 400.2[(M+H)⁺, calcd C₂₃H₂₈N₃F₂O, 400.2]; LC/MS retention time (method B):t_(R)=1.72 min.

Example 206(S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-methoxy-[2,4′-bipyridin]-2′-yl)carbamate

Part A: 6-Iodo-4-methoxypyridin-3-ol

n-BuLi (0.319 mL, 0.797 mmol) was added to the THF (4 mL) solution of2,6-diiodo-4-methoxypyridin-3-yl diethylcarbamate (0.316 g, 0.664 mmol)(Ref: J. Org. Chem. 2002, 67, 3272-3276) at −78° C. After stirring at−78° C. for 20 min, the reaction was quenched by addition of NH₄Cl(sat.). The reaction was warmed to room temperature and stirred foranother 30 min. The volatiles were removed under reduced pressure andthe crude material was partitioned between ethyl acetate and water. Theethyl acetate layer was separated, dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The residue was purified via silicagel chromatography (eluted with 0-25% ethyl acetate in hexanes) to give6-iodo-4-methoxypyridin-3-ol (0.033 g, 0.131 mmol, 20% yield). ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.95 (s, 1H), 7.14 (s, 1H), 3.92 (s, 3H), oneexchangeable proton was not observed; LCMS (ESI) m/e 251.9 [(M+H)⁺,calcd C₆H₇₁NO₂, 252.0]; LC/MS retention time (method B): t_(R)=0.85 min.

Part B: (S)-tert-butyl(1-((6-iodo-4-methoxypyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Preparation was described as Example 53, Part A. The crude material wascarried on without further purification. LCMS (ESI) m/e 465.0 [(M+H)⁺,calcd C₁₈H₃IN₂O₄, 465.1]; LC/MS retention time (method B): t_(R)=2.24min.

Part C: Boc protected (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-methoxy-[2,4′-bipyridin]-2′-yl)carbamate

Suzuki reaction was performed as described in Example 193. Obtained Bocprotected (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-methoxy-[2,4′-bipyridin]-2′-yl)carbamate(2.3 mg, 4.71 μmol, 22% yield for two steps). LCMS (ESI) m/e 489.3[(M+H)⁺, calcd C₂₅H₃₇N₄O₆, 489.2]; LC/MS retention time (method B):t_(R)=2.14 min.

Part D: (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-methoxy-[2,4′-bipyridin]-2′-yl)carbamate

TFA deprotection was performed as described in Example 32. Obtained(S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-methoxy-[2,4′-bipyridin]-2′-yl)carbamate(1.2 mg, 3.09 μmol, 66% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.51 (s,1H), 8.34 (d, J=5.1 Hz, 1H), 8.31 (s, 1H), 7.69 (d, J=5.1 Hz, 1H), 7.59(s, 1H), 3.99 (s, 3H), 3.83 (s, 2H), 3.70 (s, 3H), 3.41 (br. s., 2H),1.85-1.75 (m, 1H), 1.39 (dd, J=9.0, 5.7 Hz, 2H), 1.12 (s, 3H), 0.93 (m,6H), one exchangeable proton not observed. LCMS (ESI) m/e 389.3 [(M+H)⁺,calcd C₂₀H₂₉N₄O₄, 389.2]; LC/MS retention time (method B): t_(R)=1.56min.

Example 207

Part A: (S)-tert-butyl(1-((2′-(difluoromethyl)-4-methoxy-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Suzuki reaction was performed as described in Example 193 to afford(S)-tert-butyl(1-((2′-(difluoromethyl)-4-methoxy-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(12.9 mg, 0.028 mmol, 13% yield). LCMS (ESI) m/e 466.2 [(M+H)⁺, calcdC₂₄H₃₄F₂N₃O₄, 466.2]; LC/MS retention time (method B): t_(R)=2.65 min.

Part B:(S)-1-((2′-(difluoromethyl)-4-methoxy-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

TFA deprotection was performed as described in Example 32. Obtained(S)-1-((2′-(difluoromethyl)-4-methoxy-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(5.0 mg, 0.014 mmol, 53% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.78 (d,J=4.8 Hz, 1H), 8.38 (s, 2H), 8.26 (d, J=4.8 Hz, 1H), 7.84 (s, 1H), 7.03(t, J=1.0 Hz, 1H), 4.03 (s, 3H), 3.96 (s, 2H), 1.85-1.75 (m, 1H),1.56-1.42 (m, 2H), 1.21 (s, 3H), 0.94 (m, 6H), two exchangeable protonsnot observed. LCMS (ESI) m/e 366.2 [(M+H)⁺, calcd C₁₉H₂₆F₂N₃O₂, 366.2];LC/MS retention time (method B): t_(R)=1.70 min.

Example 208 (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)naphthalen-1-yl)pyridin-2-yl)carbamate

Part A: (S)-tert-butyl(1-((4-bromonaphthalen-1-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Prepared as described in Example 53, Part A. Obtained (S)-tert-butyl(1-((4-bromonaphthalen-1-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (37mg, 0.085 mmol, 19% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.29 (dd,J=7.8, 0.8 Hz, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.67-7.35 (m, 3H), 6.73 (d,J=8.3 Hz, 1H), 4.28 (d, J=9.0 Hz, 1H), 4.13 (d, J=9.0 Hz, 1H), 1.86 (d,J=6.5 Hz, 2H), 1.69 (dd, J=13.9, 5.1 Hz, 1H), 1.51 (s, 3H), 1.42-1.38(m, 9H), 1.01 (m, 6H); LCMS (ESI) m/e 458.1, 460.1 Br pattern [(M+Na)⁺,calcd C₂₂H₃₀BrNNaO₃, 458.1]; LC/MS retention time (method B): t_(R)=2.60min.

Part B: Boc protected (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)naphthalen-1-yl)pyridin-2-yl)carbamate

Prepared as described in Example 77, Part D. Obtained Boc protected(S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)naphthalen-1-yl)pyridin-2-yl)carbamate(12.0 mg, 0.024 mmol, 69% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.37(d, J=5.8 Hz, 2H), 8.16 (s, 1H), 7.94-7.90 (m, 1H), 7.58-7.49 (m, 2H),7.38 (d, J=8.0 Hz, 1H), 7.15 (dd, J=5.1, 1.4 Hz, 1H), 6.91 (d, J=8.0 Hz,1H), 4.33 (d, J=9.0 Hz, 1H), 4.22-4.17 (m, 1H), 3.82 (s, 3H), 1.94-1.83(m, 1H), 1.73 (br. s., 2H), 1.42 (s, 9H), 1.52 (s, 3H), 1.03 (m, 6H),two exchangeable protons not observed. LCMS (ESI) m/e 508.2 [(M+H)⁺,calcd C₂₉H₃₈N₃O₅, 508.3]; LC/MS retention time (method B): t_(R)=2.30min.

Part C:(S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)naphthalen-1-yl)pyridin-2-yl)carbamate

TFA deprotection was performed as described in Example 32. Obtained(S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)naphthalen-1-yl)pyridin-2-yl)carbamate(9.2 mg, 0.022 mmol, 95% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.40 (d,J=7.7 Hz, 1H), 8.37 (d, J=4.8 Hz, 1H), 7.95 (s, 1H), 7.85 (d, J=8.4 Hz,1H), 7.59 (t, J=8.4 Hz, 2H), 7.42 (d, J=7.7 Hz, 1H), 7.16 (d, J=5.1 Hz,1H), 7.06 (d, J=8.1 Hz, 1H), 3.94 (s, 2H), 3.67 (s, 3H), 1.86 (d, J=6.6Hz, 1H), 1.54 (dd, J=9.7, 5.7 Hz, 2H), 1.25 (s, 3H), 0.94 (m, 6H), threeexchangeable protons not observed. LCMS (ESI) m/e 408.2 [(M+H)⁺, calcdC₂₄H₃₀N₃O₃, 408.2]; LC/MS retention time (method B): t_(R)=1.78 min.

Example 209(S)-2,4-dimethyl-1-((4-(quinolin-4-yl)naphthalen-1-yl)oxy)pentan-2-amine

Part A: (S)-tert-butyl(2,4-dimethyl-1-((4-(quinolin-4-yl)naphthalen-1-yl)oxy)pentan-2-yl)carbamate

Prepared as described in Example 77, Part D. Obtained (S)-tert-butyl(2,4-dimethyl-1-((4-(quinolin-4-yl)naphthalen-1-yl)oxy)pentan-2-yl)carbamate(8.0 mg, 0.014 mmol, 40% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 9.03(d, J=4.3 Hz, 1H), 8.41 (d, J=8.5 Hz, 1H), 8.23 (d, J=8.5 Hz, 1H), 7.73(ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.56-7.48 (m, 2H), 7.43 (d, J=4.3 Hz,1H), 7.41-7.33 (m, 4H), 6.99 (d, J=7.8 Hz, 1H), 4.39 (dd, J=8.4, 4.6 Hz,1H), 4.25 (d, J=6.5 Hz, 1H), 1.97-1.88 (m, 1H), 1.81-1.72 (m, 2H), 1.57(s, 3H), 1.43 (s, 9H), 1.08-1.03 (m, 6H), one exchangeable proton notobserved; LCMS (ESI) m/e 485.2 [(M+H)⁺, calcd C₃₁H₃₇N₂O₃, 485.3]; LC/MSretention time (method B): t_(R)=2.26 min.

Part B:(S)-2,4-dimethyl-1-((4-(quinolin-4-yl)naphthalen-1-yl)oxy)pentan-2-amine

TFA deprotection was performed as described in Example 32. Obtained(S)-2,4-dimethyl-1-((4-(quinolin-4-yl)naphthalen-1-yl)oxy)pentan-2-amine(6.3 mg, 0.016 mmol, 98% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.03 (d,J=4.4 Hz, 1H), 8.44 (d, J=6.2 Hz, 1H), 8.15 (d, J=8.4 Hz, 1H), 7.78 (t,J=7.5 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H), 7.52 (d, J=4.0 Hz, 1H), 7.48-7.43(m, 2H), 7.43-7.39 (m, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz,1H), 7.13 (d, J=7.7 Hz, 1H), 4.00 (s, 2H), 1.90-1.85 (m, 1H), 1.65-1.50(m, 2H), 1.29 (s, 3H), 1.01-0.94 (m, 6H), two exchangeable protons notobserved; LCMS (ESI) m/e 385.2 [(M+H)⁺, calcd C₂₆H₂₉N₂O, 385.2]; LC/MSretention time (method B): t_(R)=1.70 min.

Example 210 (S)-methyl(4-(5-((2-amino-2,4-dimethylpentyl)oxy)pyrimidin-2-yl)pyridin-2-yl)carbamate

Part A: (S)-tert-butyl(1-((2-chloropyrimidin-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Prepared as described in Example 53, Part A. Obtained (S)-tert-butyl(1-((2-chloropyrimidin-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (25.0mg, 0.073 mmol, 49% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.32 (s,2H), 4.50 (s, 1H), 4.30 (d, J=8.5 Hz, 1H), 4.06 (d, J=8.8 Hz, 1H),1.93-1.74 (m, 2H), 1.44 (dd, J=13.9, 4.9 Hz, 1H), 1.39 (s, 9H), 1.36 (s,3H), 0.99 (dd, J=6.5, 4.5 Hz, 6H).

Part B: (S)-methyl(4-(5-((2-amino-2,4-dimethylpentyl)oxy)pyrimidin-2-yl)pyridin-2-yl)carbamate

A mixture of 2N sodium carbonate solution (0.073 mL, 0.145 mmol),1,1′-bis(diphenylphosphine)ferrocene-palladium(II)dichloridedichloromethane complex (2.97 mg, 3.64 μmol), (S)-tert-butyl(1-((2-chloropyrimidin-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate and(2-((methoxycarbonyl)amino)pyridin-4-yl)boronic acid (0.025 g, 0.128mmol) in dioxane (1 mL) (degassed) was heated at 120° C. for 4 h. Thereaction was diluted with ethyl acetate and washed with water threetimes. The ethyl acetate layer was dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The crude material was diluted withDCM (3 mL) and TFA (2 mL, 26.0 mmol) was added at room temperature. Themixture was stirred for 0.5 h at room temperature. The solvent wasremoved under reduced pressure and the crude was purified by reversephase Prep HPLC. Obtained (S)-methyl(4-(5-((2-amino-2,4-dimethylpentyl)oxy)pyrimidin-2-yl)pyridin-2-yl)carbamate(1.9 mg, 5.07 □mol, 7% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.76 (s, 1H),8.73 (s, 2H), 8.39 (d, J=5.5 Hz, 1H), 7.86 (d, J=5.1 Hz, 1H), 3.96 (s,2H), 3.71 (s, 3H), 1.86-1.78 (m, 1H), 1.46-1.36 (m, 2H), 1.15 (s, 3H),0.94 (m, 6H), three exchangeable protons not observed. LCMS (ESI) m/e360.1 [(M+H)⁺, calcd C₁₈H₂₆N₅O₃, 360.4]; LC/MS retention time (methodB): t_(R)=1.55 min.

Example 211(S)-methyl(4-(2-((2-amino-2,4-dimethylpentyl)oxy)pyrimidin-5-yl)pyridin-2-yl)carbamate

Part A: (S)-1-((5-bromopyrimidin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Potassium tert-butoxide (0.242 mL, 0.242 mmol) was added to a solutionof (S)-2-amino-2,4-dimethylpentan-1-ol (0.0265 g, 0.202 mmol) in THE(0.8 mL) at room temperature. After 5 min, 5-bromo-2-chloropyrimidine(0.047 g, 0.242 mmol) was added to the reaction mixture. The reactionwas stirred at room temperature overnight. The reaction was quenched byadding water. The volatiles were removed under reduced pressure. Theresidue was diluted with ethyl acetate and water. The ethyl acetatelayer was separated and the aqueous layer was extracted with ethylacetate. The ethyl acetate layers were combined, dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue waspurified via silica gel chromatography (eluted with methanol in DCM from0 to 10%). Obtained(S)-1-((5-bromopyrimidin-2-yl)oxy)-2,4-dimethylpentan-2-amine (0.014 g,0.050 mmol, 25% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.53 (s, 2H),4.11 (d, J=2.8 Hz, 2H), 1.87-1.75 (m, 1H), 1.66-1.56 (m, 2H), 1.48 (dd,J=5.6, 3.9 Hz, 2H), 1.22 (s, 3H), 0.98 (m, 6H). LCMS (ESI) m/e 310.1[(M+Na)⁺, calcd C₁₁H₁₈BrN₃ONa, 310.1]; LC/MS retention time (method B):t_(R)=1.67 min.

Part B: (S)-methyl(4-(2-((2-amino-2,4-dimethylpentyl)oxy)pyrimidin-5-yl)pyridin-2-yl)carbamate

Suzuki reaction was performed as described in Example 193. Obtained(S)-methyl(4-(2-((2-amino-2,4-dimethylpentyl)oxy)pyrimidin-5-yl)pyridin-2-yl)carbamate(8.4 mg, 0.023 mmol, 47% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.60(s, 2H), 8.49 (s, 1H), 8.31 (dd, J=5.3, 0.5 Hz, 1H), 8.18 (s, 1H), 7.11(dd, J=5.4, 1.6 Hz, 1H), 3.85 (s, 3H), 3.84-3.69 (m, 2H), 2.00-1.92 (m,1H), 1.91-1.78 (m, 1H), 1.56 (dd, J=14.3, 5.0 Hz, 1H), 1.36 (s, 3H),1.02 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.5 Hz, 3H), two exchangeable protonsnot observed; LCMS (ESI) m/e 359.9 [(M+H)⁺, calcd C₁₈H₂₆N₅O₃, 360.2];LC/MS retention time (method B): t_(R)=1.76 min.

Example 212(S)-2,4-dimethyl-1-((2′,4,6-trimethyl-[2,4′-bipyridin]-5-yl)oxy)pentan-2-amine

Suzuki reaction was performed as described in Example 193. Obtained(S)-2,4-dimethyl-1-((2′,4,6-trimethyl-[2,4′-bipyridin]-5-yl)oxy)pentan-2-amine(10.3 mg, 0.031 mmol, 57% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.57(d, J=5.3 Hz, 1H), 7.75 (s, 1H), 7.62 (dd, J=5.1, 1.4 Hz, 1H), 7.46 (s,1H), 3.66-3.55 (m, 2H), 2.64 (s, 3H), 2.60 (s, 3H), 2.39 (s, 3H), 2.08(br. S, 2H); 1.88 (tt, J=12.7, 6.4 Hz, 1H), 1.54 (d, J=5.8 Hz, 2H), 1.34(s, 3H), 1.04 (d, J=6.5 Hz, 3H), 1.02 (d, J=6.8 Hz, 3H); LCMS (ESI) m/e328.1 [(M+H)⁺, calcd C₂₀H₃₀N₃O, 328.2]; LC/MS retention time (method B):t_(R)=1.44 min.

Example 213(S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4,6-dimethyl-[2,4′-bipyridin]-2′-yl)carbamate

Suzuki reaction was performed as described in Example 193. Obtained(S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4,6-dimethyl-[2,4′-bipyridin]-2′-yl)carbamate(8.0 mg, 0.021 mmol, 38% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.52(br. s, 2H), 8.33-8.17 (m, 1H), 7.68 (dd, J=5.3, 1.5 Hz, 1H), 7.53 (s,1H), 3.85 (s, 3H), 3.65-3.52 (m, 2H), 2.60 (s, 3H), 2.56 (br.s, 2H),2.38 (s, 3H), 1.88 (dquin, J=12.7, 6.4 Hz, 1H), 1.54 (d, J=5.3 Hz, 2H),1.34 (s, 3H), 1.04 (d, J=6.8 Hz, 3H), 1.02 (d, J=6.5 Hz, 3H); LCMS (ESI)m/e 387.1 [(M+H)⁺, calcd C₂₁H₃₁N₄O₃, 387.2]; LC/MS retention time(method B): t_(R)=1.54 min.

Example 214(S)-2,4-dimethyl-1-(4-(quinazolin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine

Prepared as described in Example 19. Obtained(S)-2,4-dimethyl-1-(4-(quinazolin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine(8.5 mg, 0.020 mmol, 19% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.34 (s,1H), 8.17-8.03 (m, 5H), 7.79 (t, J=7.5 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H),3.94 (d, J=7.3 Hz, 2H), 1.85-1.76 (m, 1H), 1.43 (m, 2H), 1.16 (s, 3H),0.97-0.89 (m, 6H), two exchangeable protons not observed; LCMS (ESI) m/e404.2 [(M+H)⁺, calcd C₂₂H₂₅F₃N₃O, 404.4]; LC/MS retention time (methodB): t_(R)=2.01 min.

Example 215(S)-1-(4-(3,6-dihydro-2H-pyran-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

Part A: 3,6-Dihydro-2H-pyran-4-yl trifluoromethanesulfonate

KHMDS (6.66 mL, 3.33 mmol) was added to the THF (7 mL) solution ofdihydro-2H-pyran-4(3H)-one (0.2224 g, 2.221 mmol) and1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(0.952 g, 2.67 mmol) at −78° C. The reaction was stirred for 30 min. Thereaction was diluted with diethyl ether and washed with water (3×). Thediethyl ether layer was separated, dried (Na₂SO₄), filtered andconcentrated. The crude material was carried on without furtherpurification.

Part B: (S)-tert-butyl(2,4-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)pentan-2-yl)carbamate

Prepared as described in Example 77, Part C. The crude material wascarried on without further purification. LCMS (ESI) m/e 523.2 [(M+Na)⁺,calcd C₂₅H₃₉BF₃NO₅Na, 524.3]; LC/MS retention time (method B):t_(R)=2.61 min.

Part C:(S)-1-(4-(3,6-dihydro-2H-pyran-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

A mixture of 2N sodium carbonate solution (0.106 mL, 0.212 mmol),1,1′-bis(diphenylphosphine)ferrocene-palladium(II)dichloridedichloromethane complex (6.06 mg, 7.42 μmol), 3,6-dihydro-2H-pyran-4-yltrifluoromethanesulfonate (98 mg, 0.424 mmol) and (S)-tert-butyl(2,4-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)pentan-2-yl)carbamate(53.1 mg, 0.106 mmol) in dioxane (2 mL) (degassed) was heated at 120° C.for 5 h. The reaction was diluted with ethyl acetate and washed withwater three times. The ethyl acetate layer was dried (Na₂SO₄), filteredand concentrated under reduced pressure. The residue was diluted withDCM (3 mL) and TFA (2 mL, 26.0 mmol) was added at room temperature. Thereaction was stirred at room temperature for 0.5 h. The solvent wasremoved under reduced pressure and the residue was purified by reversephase Prep HPLC to give(S)-1-(4-(3,6-dihydro-2H-pyran-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(2.7 mg, 0.213 mmol, 7% yield over three steps). ¹H NMR (500 MHz,DMSO-d₆) δ 7.69 (d, J=8.4 Hz, 1H), 7.61 (s, 1H), 7.20 (d, J=8.4 Hz, 1H),6.24 (m, 1H), 4.21 (d, J=2.6 Hz, 2H), 3.83-3.79 (m, 4H), 2.42 (br. s.,2H), 1.80-1.72 (m, 1H), 1.42-1.37 (m, 2H), 1.12 (s, 3H), 0.89 (m, 6H),two exchangeable protons not observed; LCMS (ESI) m/e 358.3 [(M+H)⁺,calcd C₁₉H₂₇F₃NO₂, 358.2]; LC/MS retention time (method B): t_(R)=1.99min.

Example 216(S)-2,4-dimethyl-1-(4-(2-methylquinolin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine

A mixture of 2N sodium carbonate solution (0.157 mL, 0.314 mmol),1,1′-bis(diphenylphosphine)ferrocene-palladium(II)dichloridedichloromethane complex (8.97 mg, 10.99 μmol), (S)-tert-butyl(2,4-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)pentan-2-yl)carbamate(0.079 g, 0.157 mmol) (prepared in Example 215, Part B) and4-chloro-2-methylquinoline (0.05 ml, 0.248 mmol) in dioxane (1 mL)(degassed) was heated at 120° C. for 5 h. The reaction was diluted withethyl acetate and washed with water three times. The ethyl acetate layerwas dried (Na₂SO₄), filtered and concentrated under reduced pressure.The residue was diluted with DCM (3 mL) and was added TFA (2 mL, 26.0mmol) at room temperature. The reaction was stirred at room temperaturefor 0.5 h. The solvent was removed under reduced pressure and thematerial was purified by reverse phase HPLC/MS to afford(S)-2,4-dimethyl-1-(4-(2-methylquinolin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine(14.8 mg, 0.035 mmol, 22% yield). H NMR (500 MHz, DMSO-d₆) δ 8.02 (d,J=8.4 Hz, 1H), 7.83-7.73 (m, 4H), 7.55 (t, J=7.5 Hz, 1H), 7.44-7.41 (m,2H), 3.94-3.87 (m, 2H), 3.47 (br. s., 2H), 2.70 (s, 3H), 1.87-1.79 (m,1H), 1.42 (d, J=5.5 Hz, 2H), 1.15 (s, 3H), 0.95 (d, J=2.9 Hz, 3H), 0.93(d, J=2.9 Hz, 3H); LCMS (ESI) m/e 417.3 [(M+H)⁺, calcd C₂₄H₂₈F₃N₂O,417.2]; LC/MS retention time (method B): t_(R)=2.26 min.

Example 217(S)-1-(4-(6-chloroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine

Preparation was described as Example 19. Intermediate6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline wasprepared as described in Example 77, Part B and Part C. Obtained(S)-1-(4-(6-chloroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine(3.9 mg, 8.66 μmol, 7% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.98 (d,J=4.4 Hz, 1H), 8.16 (d, J=8.8 Hz, 1H), 7.85 (dd, J=9.0, 2.4 Hz, 2H),7.79 (d, J=2.6 Hz, 2H), 7.59 (d, J=4.4 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H),3.97-3.89 (m, 2H), 1.83 (dt, J=12.7, 6.1 Hz, 1H), 1.43 (d, J=4.8 Hz,2H), 1.16 (s, 3H), 0.94 (m, 6H); LCMS (ESI) m/e 419.9 [(M-NH₂)+, calcdC₂₃H₂₂ClF₃NO, 420.1]; LC/MS retention time (method B): t_(R)=2.07 min.

Example 218(S)-1-((5-(5,7-difluoroquinolin-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: 5-Bromo-3-(trifluoromethyl)pyridin-2-ol

NBS (2.334 g, 13.11 mmol) was added portionwise to a solution of3-(trifluoromethyl)pyridin-2-ol (1.6449 g, 10.09 mmol) in THE (15 mL) atroom temperature. The reaction was stirred at room temperature over theweekend. The reaction was diluted with ethyl acetate and washed withwater three times. The ethyl acetate layer was separated, dried(Na₂SO₄), filtered and concentrated under reduced pressure to give crude5-bromo-3-(trifluoromethyl)pyridin-2-ol (2.12 g, 6.57 mmol, 65% yield)as a yellow solid. The material was carried on without furtherpurification. LCMS (ESI) m/e 241.8 [(M+H)⁺, calcd C₆H₄BrF₃NO, 241.9];LC/MS retention time (method B): t_(R)=1.57 min.

Part B: (S)-tert-butyl(1-((5-bromo-3-(trifluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

A mixture of potassium carbonate (0.113 g, 0.814 mmol), (S)-tert-butyl4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(0.1593 g, 0.543 mmol) and 5-bromo-3-(trifluoromethyl)pyridin-2-ol(0.197 g, 0.814 mmol) in DMF (2 mL) was heated at 80° C. overnight. Thereaction was diluted with ethyl acetate and washed with water threetimes. The ethyl acetate layer was separated, dried (Na₂SO₄), filteredand concentrated under reduced pressure. The residue was purified bysilica gel chromatography (eluted with ethyl acetate in hexane from 0 to10%) to give (S)-tert-butyl(1-((5-bromo-3-(trifluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(0.059 g, 0.111 mmol, 20% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.34(d, J=2.5 Hz, 1H), 7.95 (d, J=2.5 Hz, 1H), 4.59-4.52 (m, 2H), 4.39 (d,J=10.3 Hz, 1H), 1.89-1.72 (m, 2H), 1.54 (d, J=8.8 Hz, 1H), 1.39 (s, 9H),1.37 (s, 3H), 0.97 (m, 6H); ¹⁹F NMR (376 MHz, CHLOROFORM-d) δ −64.11 (s,3F). LCMS (ESI) m/e 476.9 [(M+Na)⁺, calcd C₁₈H₂₆BrF₃N₂O₃Na, 477.1];LC/MS retention time (method B): t_(R)=2.54 min.

Part C: (S)-tert-butyl(1-((5-(5,7-difluoroquinolin-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Prepared as described in Example 193. Obtained (S)-tert-butyl(1-((5-(5,7-difluoroquinolin-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(26.0 mg, 0.048 mmol, 80% yield). LCMS (ESI) m/e 540.2 [(M+H)⁺, calcdC₂₇H₃₁F₅N₃O₃, 540.2]; LC/MS retention time (method B): t_(R)=2.53 min.

Part D:(S)-1-((5-(5,7-difluoroquinolin-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

TFA deprotection was performed as described in Example 32. Obtained(S)-1-((5-(5,7-difluoroquinolin-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(12.5 mg, 0.025 mmol, 56% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.34 (s,1H), 8.17-8.03 (m, 5H), 7.79 (t, J=7.5 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H),3.94 (d, J=7.3 Hz, 2H), 1.85-1.76 (m, 1H), 1.43 (m, 2H), 1.16 (s, 3H),0.97-0.89 (m, 6H). LCMS (ESI) m/e 440.1 [(M+H)⁺, calcd C₂₂H₂₃F₅N₃O,440.2]; LC/MS retention time (method B): t_(R)=2.04 min.

Example 219(S)-2,4-dimethyl-1-((5-(quinolin-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)pentan-2-amine

Prepared as described in Example 218. Obtained(S)-2,4-dimethyl-1-((5-(quinolin-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)pentan-2-amine(6.1 mg, 0.015 mmol, 60% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.99 (d, J=4.4 Hz, 1H), 8.63 (s, 1H), 8.31 (s, 1H), 8.14 (d,J=8.4 Hz, 1H), 7.88-7.82 (m, 2H), 7.66 (t, J=7.5 Hz, 1H), 7.60 (d, J=4.4Hz, 1H), 4.25-4.18 (m, 2H), 1.84 (dt, J=12.7, 6.1 Hz, 1H), 1.42 (d,J=5.5 Hz, 2H), 1.15 (s, 3H), 0.94 (m, 6H), two exchangeable protons notobserved; LCMS (ESI) m/e 404.0 [(M+H)⁺, calcd C₂₂H₂₅F₃N₃O, 404.4]; LC/MSretention time (method B): t_(R)=1.77 min.

Example 220 (S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-(trifluoromethyl)-[3,4′-bipyridin]-2′-yl)carbamate

Prepared as described in Example 218. Obtained (S)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-(trifluoromethyl)-[3,4′-bipyridin]-2′-yl)carbamate(13.8 mg, 0.032 mmol, 96% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.35 (br. s., 1H), 8.79 (s, 1H), 8.38-8.32 (m, 2H), 8.11 (s,1H), 7.48 (d, J=5.1 Hz, 1H), 4.17 (q, J=10.3 Hz, 2H), 3.38 (br. s., 3H),1.85-1.74 (m, 1H), 1.38 (d, J=5.5 Hz, 2H), 1.11 (s, 3H), 0.91 (m, 6H),two exchangeable protons not observed; LCMS (ESI) m/e 427.0 [(M+H)⁺,calcd C₂H₂₆F₃N₄O₃, 427.2]; LC/MS retention time (method B): t_(R)=1.84min.

Example 221(S)-2,4-dimethyl-1-((2′-methyl-5-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)oxy)pentan-2-amine

Prepared as described in Example 218. Obtained(S)-2,4-dimethyl-1-((2′-methyl-5-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)oxy)pentan-2-amine(4.6 mg, 0.012 mmol, 68% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.87 (s,1H), 8.52 (d, J=5.1 Hz, 1H), 8.46 (s, 1H), 7.72 (s, 1H), 7.62 (d, J=4.0Hz, 1H), 4.16 (q, J=10.1 Hz, 2H), 2.54 (s, 3H), 1.84-1.75 (m, 1H), 1.37(d, J=5.5 Hz, 2H), 1.10 (s, 3H), 0.91 (m, 6H), two exchangeable protonsnot observed; LCMS (ESI) m/e 368.0 [(M+H)⁺, calcd C₁₉H₂₅F₃N₃O, 368.2];LC/MS retention time (method B): t_(R)=1.57 min.

Example 222(S)-1-((5-(6-chloroquinolin-4-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: 4-Bromo-6-chloroquinoline

Prepared as described in Example 77, Part B. Obtained4-Bromo-6-chloroquinoline (0.322 g, 1.33 mmol, 76% yield). H NMR (400MHz, CHLOROFORM-d) δ 8.68 (d, J=4.8 Hz, 1H), 8.21 (d, J=2.3 Hz, 1H),8.07 (d, J=8.8 Hz, 1H), 7.76-7.70 (m, 2H). LCMS (ESI) m/e 243.7 [(M+H)⁺,calcd C₉H₅BrNCl, 243.5]; LC/MS retention time (method B): t_(R)=2.07min.

Part B:7-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Prepared as described in Example 77, Part C. Carried on without furtherpurification. LCMS (ESI) m/e 207.9 [(M-NH₂)+, calcd C₉H₇BNClO₂, 207.0];LC/MS retention time (method B): t_(R)=1.21 min.

Part C:(S)-1-((5-(6-chloroquinolin-4-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Intermediate(S)-1-((5-bromo-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amineprepared as in Example 52, Part A. Suzuki reaction was performed asdescribed in Example 193. Obtained(S)-1-((5-(6-chloroquinolin-4-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(56.7 mg, 0.143 mmol, 26% yield over two steps). ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.94 (d, J=4.5 Hz, 1H), 8.14 (d, J=9.0 Hz, 1H), 8.08 (d,J=1.8 Hz, 1H), 7.82 (d, J=2.3 Hz, 1H), 7.69 (dd, J=8.8, 2.3 Hz, 1H),7.57-7.54 (m, 1H), 7.32 (d, J=4.5 Hz, 1H), 4.64-4.42 (m, 2H), 1.93-1.75(m, 3H), 1.54 (s, 3H), 1.03 (d, J=6.3 Hz, 3H), 1.01 (d, J=6.3 Hz, 3H),two exchangeable protons not observed; LCMS (ESI) m/e 366.9 [(M-NH₂)+,calcd C₂₂H₂₄N₂ClO, 367.2]; LC/MS retention time (method B): t_(R)=1.88min.

Example 223(S)-1-((5-(6-fluoroquinolin-4-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Intermediate(S)-1-((5-bromo-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amineprepared as described in Example 52, Part A. The corresponding borolatewas prepared as described in Example 77, Part C. Suzuki reaction wasperformed as described in Example 193. Obtained(S)-1-((5-(6-fluoroquinolin-4-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(9.7 mg, 0.026 mmol, 14% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.92(d, J=4.5 Hz, 1H), 8.31-8.16 (m, 1H), 8.12 (d, J=2.0 Hz, 1H), 7.61-7.49(m, 3H), 7.34 (d, J=4.3 Hz, 1H), 4.27-4.18 (m, 2H), 2.35 (s, 3H),1.93-1.78 (m, 1H), 1.63-1.49 (m, 2H), 1.29 (s, 3H), 1.03 (d, J=6.8 Hz,3H), 1.01 (d, J=6.8 Hz, 3H), two exchangeable protons not observed; LCMS(ESI) m/e 368.2 [(M+H)⁺, calcd C₂₂H₂₇N₃FO, 368.2]; LC/MS retention time(method B): t_(R)=1.78 min.

Example 224

Part A: (S)-tert-butyl(1-((5-bromo-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Prepared as described in Example 53, Part A. obtained(S)-1-((5-(5,7-difluoroquinolin-4-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(3.06 g, 7.32 mmol, 86% yield). LCMS (ESI) m/e 422.9 [(M+Na)⁺, calcdC₁₈H₂₉BrN₂O₃Na, 423.1]; LC/MS retention time (method B): t_(R)=2.48 min.

Part B: (S)-tert-butyl(1-((5-(5,7-difluoroquinolin-4-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Suzuki reaction was performed as described in Example 193. Obtained(S)-tert-butyl(1-((5-(5,7-difluoroquinolin-4-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(43.8 mg, 0.090 mmol, 59% yield). LCMS (ESI) m/e 486.1 [(M+H)⁺, calcdC₂₇H₃₄N₃F₂O₃, 486.3]; LC/MS retention time (method B): t_(R)=2.44 min.

Part C:(S)-1-((5-(5,7-difluoroquinolin-4-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

TFA deprotection was performed as described in Example 32. Obtained(S)-1-((5-(5,7-difluoroquinolin-4-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(33.9 mg, 0.088 mmol, 98% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.00 (d,J=4.4 Hz, 1H), 8.10 (s, 1H), 7.79 (d, J=9.5 Hz, 1H), 7.75 (br. s., 1H),7.61-7.52 (m, 1H), 7.45 (d, J=4.4 Hz, 1H), 4.45-4.31 (m, 2H), 2.33 (s,3H), 1.89-1.74 (m, 2H), 1.66 (dd, J=14.1, 5.3 Hz, 1H), 1.42 (s, 3H),0.98 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H), two exchangeable protonsnot observed; LCMS (ESI) m/e 386.3 [(M+H)⁺, calcd C₂₂H₂₆N₃F₂O, 386.2];LC/MS retention time (method B): t_(R)=1.84 min.

Example 225(S)-1-((5-(7-chloroquinolin-4-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Intermediate(S)-1-((5-bromo-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-aminewas prepared as described in Example 52, Part A. The correspondingborolate was prepared as described in Example 77, Part C. Suzukireaction was performed as described in Example 193. Obtained(S)-1-((5-(7-chloroquinolin-4-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(22.5 mg, 0.058 mmol, 51% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.98 (d,J=4.4 Hz, 1H), 8.17 (s, 2H), 7.96-7.91 (m, 1H), 7.81 (s, 1H), 7.66 (dd,J=9.0, 2.0 Hz, 1H), 7.53 (d, J=4.4 Hz, 1H), 4.15-4.07 (m, 2H), 2.30 (s,3H), 1.87-1.79 (m, 1H), 1.45 (t, J=6.4 Hz, 2H), 1.17 (s, 3H), 0.95 (m,6H), two exchangeable protons not observed; LCMS (ESI) m/e 384.3[(M+H)⁺, calcd C₂₂H₂₇N₃ClO, 384.2]; LC/MS retention time (method B):t_(R)=1.98 min.

Example 226(S)-1-((6-(5,7-difluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Part A:(S)-1-((6-chloro-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

A mixture of TFA (0.4 mL, 5.19 mmol) and (S)-tert-butyl(1-((6-chloro-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(0.064 g, 0.179 mmol, 0.179 mmol) in CH₂Cl₂ (4 mL) was stirred at roomtemperature for 4 h. LCMS showed complete conversion to(S)-1-((6-chloro-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine.The solvent was removed via vacuum and the material was used withoutfurther purification. LCMS (ESI) m/e 257.1 [(M+H)⁺, calcd C13H₂₂ClN₂O,257.1]; LC/MS retention time (method B): t_(R)=1.64 min.

Part B:(S)-1-((6-(5,7-difluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Suzuki coupling was performed as described in Example 77, Part D.Obtained(S)-1-((6-(5,7-difluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(12.2 mg, 0.031 mmol, 43% yield). ¹H NMR (500 MHz, DMSO-d6) δ 9.01 (d,J=4.4 Hz, 1H), 8.30 (s, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.53 (br. s., 1H),7.49 (d, J=4.4 Hz, 1H), 7.47 (s, 1H), 3.94 (s, 2H), 2.31 (s, 3H),1.88-1.80 (m, 1H), 1.48 (dd, J=13.0, 5.3 Hz, 2H), 1.20 (s, 3H), 0.95 (m,6H), two exchangeable protons not observed; LCMS (ESI) m/e 386.0[(M+H)⁺, calcd C₂₂H₂₆F₂N₃O, 386.2]; LC/MS retention time (method B):t_(R)=1.79 min.

Example 227(S)-1-((6-(7-fluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 226. Obtained(S)-1-((6-(7-fluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(6.0 mg, 0.016 mmol, 63% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (d,J=4.5 Hz, 1H), 8.47 (s, 1H), 8.34 (dd, J=9.3, 6.3 Hz, 1H), 7.82 (dd,J=10.3, 2.8 Hz, 1H), 7.67 (s, 1H), 7.59 (d, J=4.5 Hz, 1H), 7.55 (td,J=8.9, 2.8 Hz, 1H), 4.10 (s, 2H), 2.37 (s, 3H), 1.86-1.78 (m, 1H), 1.63(br. s., 1H), 1.57-1.50 (m, 1H), 1.30 (s, 3H), 0.95 (dd, J=11.7, 6.7 Hz,6H), two exchangeable protons not observed; LCMS (ESI) m/e 368.0[(M+H)⁺, calcd C₂₂H₂₇FN₃O, 368.2]; LC/MS retention time (method B):t_(R)=1.67 min.

Example 228(S)-1-((2′,4-dimethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((2′,4-dimethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Suzuki coupling was performed as described in Example 77, Part D. Thecrude was used in the next reaction without purification. LCMS (ESI) m/e414.0 [(M+H)⁺, calcd C₂₄H₃₆N₃O₃, 414.3]; LC/MS retention time (methodB): t_(R)=2.02 min.

Part B:(S)-1-((2′,4-dimethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

TFA deprotection as described in Example 32. Obtained(S)-1-((2′,4-dimethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(2.2 mg, 6.95 μmol, 17% yield over two steps). ¹H NMR (600 MHz, DMSO-d₆)δ 8.50 (d, J=5.1 Hz, 1H), 8.34 (s, 1H), 7.96 (s, 1H), 7.86 (s, 1H), 7.78(d, J=5.1 Hz, 1H), 3.88 (br. s., 2H), 2.54 (s, 3H), 2.31 (s, 3H), 1.82(br. s., 1H), 1.45-1.38 (m, 2H), 1.15 (s, 3H), 0.93 (m, 6H), twoexchangeable protons not observed; LCMS (ESI) m/e 314.1 [(M+H)⁺, calcdC₁₉H₂N₃O, 314.2]; LC/MS retention time (method B): t_(R)=1.50 min.

Example 229(S)-1-((6-(6-chloroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((6-(6-chloroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Suzuki coupling was performed as described in Example 77, Part D. Thecrude was used in the next reaction without purification. LCMS (ESI) m/e483.9 [(M+H)⁺, calcd C₂₇H₃₅ClN₃O₃, 484.2]; LC/MS retention time (methodB): t_(R)=2.24 min.

Part B:(S)-1-((6-(6-chloroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

TFA deprotection as described in Example 32. Obtained(S)-1-((6-(6-chloroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(6.8 mg, 0.017 mmol, 16% yield over two steps). ¹H NMR (500 MHz,DMSO-d₆) δ 9.00 (d, J=4.4 Hz, 1H), 8.48 (s, 1H), 8.40 (d, J=2.2 Hz, 1H),8.12 (d, J=9.2 Hz, 1H), 7.82 (dd, J=8.8, 2.2 Hz, 1H), 7.71 (s, 1H), 7.69(d, J=4.8 Hz, 1H), 3.95 (s, 2H), 2.35 (s, 3H), 1.84 (d, J=6.2 Hz, 1H),1.45 (t, J=6.6 Hz, 2H), 1.18 (s, 3H), 0.95 (m, 6H), two exchangeableprotons not observed; LCMS (ESI) m/e 383.9 [(M+H)⁺, calcd C₂₂H₂₇ClN₃O,384.2]; LC/MS retention time (method B): t_(R)=1.81 min.

Example 230(S)-1-((6-(6-fluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((6-(6-fluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Suzuki coupling was performed as described in Example 77, Part D.Obtained (S)-tert-butyl(1-((6-(6-fluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(33.2 mg, 0.035 mmol, 35% yield). LCMS (ESI) m/e 468.2 [(M+H)⁺, calcdC₂₇H₃₅FN₃O₃, 468.3]; LC/MS retention time (method B): t_(R)=2.22 min.

Part B:(S)-1-((6-(6-fluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

TFA deprotection as described in Example 32. Obtained(S)-1-((6-(6-fluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(21.7 mg, 0.058 mmol, 82% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.98 (d,J=4.4 Hz, 1H), 8.53 (s, 1H), 8.18 (dd, J=9.2, 5.5 Hz, 1H), 8.07 (dd,J=11.0, 2.9 Hz, 1H), 7.73 (s, 2H), 7.69 (d, J=4.4 Hz, 1H), 4.15 (d,J=4.4 Hz, 2H), 2.39 (s, 3H), 1.89-1.81 (m, 1H), 1.66 (d, J=5.1 Hz, 1H),1.56 (dd, J=14.1, 5.3 Hz, 1H), 1.33 (s, 3H), 0.99 (d, J=6.6 Hz, 3H),0.96 (d, J=6.6 Hz, 3H), two exchangeable protons not observed; LCMS(ESI) m/e 368.2 [(M+H)⁺, calcd C₂₂H₂₇FN₃O, 368.2]; LC/MS retention time(method B): t_(R)=1.67 min.

Example 231(S)-1-((6-(7-chloroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((6-(7-chloroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Suzuki coupling was performed as described in Example 77, Part D. Thecrude was used in the next reaction without purification. LCMS (ESI) m/e484.2 [(M+H)⁺, calcd C₂₇H₃₅ClN₃O₃, 484.2]; LC/MS retention time (methodB): t_(R)=2.32 min.

Part B:(S)-1-((6-(7-chloroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

TFA deprotection as described in Example 32. Obtained (S)-tert-butyl(1-((6-(7-chloroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(15.5 mg, 0.039 mmol, 34% yield over two steps). ¹H NMR (500 MHz,DMSO-d₆) δ 8.98 (d, J=4.4 Hz, 1H), 8.53 (s, 1H), 8.18 (dd, J=9.2, 5.5Hz, 1H), 8.07 (dd, J=11.0, 2.9 Hz, 1H), 7.73 (s, 2H), 7.69 (d, J=4.4 Hz,1H), 4.15 (d, J=4.4 Hz, 2H), 2.39 (s, 3H), 1.89-1.81 (m, 1H), 1.66 (d,J=5.1 Hz, 1H), 1.56 (dd, J=14.1, 5.3 Hz, 1H), 1.33 (s, 3H), 0.99 (d,J=6.6 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H), two exchangeable protons notobserved; LCMS (ESI) m/e 384.1 [(M+H)⁺, calcd C₂₂H₂₇ClN₃O, 384.2]; LC/MSretention time (method B): t_(R)=1.84 min.

Example 232(S)-1-((6-(7-fluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((6-(7-fluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Suzuki coupling was performed as described in Example 77, Part D.Obtained (S)-tert-butyl(1-((6-(7-fluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(56 mg, 0.055 mmol, 27% yield). LCMS (ESI) m/e 468.0 [(M+H)⁺, calcdC₂₇H₃₅FN₃O₃, 468.3]; LC/MS retention time (method B): t_(R)=2.24 min.

Part B:(S)-1-((6-(7-fluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

TFA deprotection as described in Example 32. Obtained(S)-1-((6-(7-fluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(36.4 mg, 0.095 mmol, 89% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (d,J=4.5 Hz, 1H), 8.47 (s, 1H), 8.34 (dd, J=9.3, 6.3 Hz, 1H), 7.82 (dd,J=10.3, 2.8 Hz, 1H), 7.67 (s, 1H), 7.59 (d, J=4.5 Hz, 1H), 7.55 (td,J=8.9, 2.8 Hz, 1H), 4.10 (s, 2H), 2.37 (s, 3H), 1.86-1.78 (m, 1H), 1.63(br. s., 1H), 1.57-1.50 (m, 1H), 1.30 (s, 3H), 0.95 (m, 6H), twoexchangeable protons not observed; LCMS (ESI) m/e 368.0 [(M+H)⁺, calcdC₂₂H₂₇FN₃O, 368.2]; LC/MS retention time (method B): t_(R)=1.67 min.

Example 233(S)-1-((4-chloro-6-(5,7-difluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((4-chloro-6-(5,7-difluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Suzuki coupling was performed as described in Example 77, Part D.Obtained (S)-tert-butyl(1-((4-chloro-6-(5,7-difluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(50.6 mg, 0.062 mmol, 62% yield). LCMS (ESI) m/e 506.2 [(M+H)⁺, calcdC₂₆H₃₁ClF₂N₃₃, 506.2]; LC/MS retention time (method B): t_(R)=2.43 min.

Part B:(S)-1-((4-chloro-6-(5,7-difluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

TFA deprotection as described in Example 32. Obtained(S)-1-((4-chloro-6-(5,7-difluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(16.2 mg, 0.040 mmol, 40% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.04 (d,J=4.4 Hz, 1H), 8.55 (s, 1H), 7.88 (s, 1H), 7.81 (d, J=9.5 Hz, 1H),7.61-7.53 (m, 2H), 4.04 (s, 2H), 1.88-1.77 (m, 1H), 1.52-1.40 (m, 2H),1.20 (s, 3H), 0.95 (m, 6H), two exchangeable protons not observed; LCMS(ESI) m/e 406.1 [(M+H)⁺, calcd C₂₁H₂₃ClF₂N₃O, 406.1]; LC/MS retentiontime (method A): t_(R)=1.82 min.

Example 234(S)-1-((4-chloro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((4-chloro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Suzuki coupling was performed as described in Example 77, Part D.Obtained (S)-tert-butyl(1-((4-chloro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(24.6 mg, 0.059 mmol, 25% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.72(br. s., 2H), 8.41 (s, 1H), 7.83 (s, 3H), 4.59 (s, 1H), 4.41 (d, J=8.8Hz, 1H), 4.21 (d, J=8.8 Hz, 1H), 1.95-1.80 (m, 2H), 1.56 (dd, J=13.9,4.9 Hz, 1H), 1.44 (s, 3H), 1.40 (s, 9H), 1.01 (m, 6H). LCMS (ESI) m/e420.2 [(M+H)⁺, calcd C₂₂H₃₁ClN₃O₃, 420.2]; LC/MS retention time (methodA): t_(R)=2.07 min.

Part B:(S)-1-((4-chloro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

TFA deprotection as described in Example 32. Obtained(S)-1-((4-chloro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(7.2 mg, 0.022 mmol, 96% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.68 (d,J=5.9 Hz, 2H), 8.64 (s, 1H), 8.35 (s, 1H), 8.04 (d, J=5.9 Hz, 2H), 4.18(s, 2H), 1.85-1.77 (m, 1H), 1.66-1.60 (m, 1H), 1.52 (dd, J=14.1, 5.3 Hz,1H), 1.29 (s, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H); LCMS(ESI) m/e 303.1 [(M-NH₂)+, calcd C₁₇H₂₀ClN₂O, 303.1]; LC/MS retentiontime (method B): t_(R)=1.44 min.

Example 235(S)-1-((4-chloro-6-(6-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((4-chloro-6-(6-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Suzuki coupling was performed as described in Example 77, Part D.Obtained (S)-tert-butyl(1-((4-chloro-6-(6-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(62.0 mg, 0.109 mmol, 45% yield). LCMS (ESI) m/e 488.2 [(M+H)⁺, calcdC₂₆H₃₂ClFN₃O₃, 488.2]; LC/MS retention time (method B): t_(R)=2.37 min.

Part B:(S)-1-((4-chloro-6-(6-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

TFA deprotection as described in Example 32. Obtained(S)-1-((4-chloro-6-(6-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(42.3 mg, 0.109 mmol, 86% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.99 (d,J=4.4 Hz, 1H), 8.76 (s, 1H), 8.19 (dd, J=9.2, 5.9 Hz, 1H), 8.07 (s, 1H),8.03 (dd, J=11.0, 2.9 Hz, 1H), 7.77-7.71 (m, 2H), 4.30 (s, 2H), 1.86(dt, J=12.5, 6.2 Hz, 1H), 1.77-1.69 (m, 1H), 1.60 (dd, J=14.1, 5.7 Hz,1H), 1.37 (s, 3H), 0.97 (m, 6H), two exchangeable protons not observed;LCMS (ESI) m/e 388.1 [(M+H)⁺, calcd C₂₁H₂₄ClFN₃O, 388.2]; LC/MSretention time (method B): t_(R)=1.75 min.

Example 236(S)-1-((4-chloro-6-(quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 233. Obtained(S)-1-((4-chloro-6-(quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(2.6 mg, 6.82 □mol, 16% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.00 (d,J=4.4 Hz, 1H), 8.70 (s, 1H), 8.21 (d, J=8.4 Hz, 1H), 8.12 (d, J=8.4 Hz,1H), 8.00 (s, 1H), 7.82 (t, J=7.3 Hz, 1H), 7.69-7.56 (m, 2H), 4.09 (s,2H), 1.86 (dt, J=13.0, 6.3 Hz, 1H), 1.49 (qd, J=13.9, 5.5 Hz, 2H), 1.22(s, 3H), 0.96 (t, J=6.8 Hz, 6H), two exchangeable protons not observed;LCMS (ESI) m/e 370.0 [(M+H)⁺, calcd C₂₁H₂₅ClN₃O, 370.2]; LC/MS retentiontime (method B): t_(R)=1.75 min.

Example 237 (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-chloro-[2,4′-bipyridin]-2′-yl)carbamate

Suzuki coupling was performed as described in Example 77, Part D.Obtained (S)-methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-chloro-[2,4′-bipyridin]-2′-yl)carbamate(8.1 mg, 0.020 mmol, 35% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 8.59 (s,1H), 8.52 (s, 1H), 8.34 (d, J=5.5 Hz, 1H), 8.19 (s, 1H), 7.67 (d, J=5.5Hz, 1H), 4.01-3.96 (m, 2H), 3.71 (s, 3H), 1.85-1.77 (m, 1H), 1.45-1.36(m, 2H), 1.17-1.12 (m, 3H), 0.95-0.89 (m, 6H), three exchangeableprotons not observed; LCMS (ESI) m/e 393.0 [(M+H)⁺, calcd C₁₉H₂₆ClN₄O₃,393.2]; LC/MS retention time (method B): t_(R)=1.63 min.

Example 238(S)-1-((4-chloro-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((4-chloro-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Suzuki coupling was performed as described in Example 77, Part D.Obtained (S)-tert-butyl(1-((4-chloro-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(107.4 mg, 0.247 mmol, 49% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.57(d, J=5.0 Hz, 1H), 8.38 (s, 1H), 7.80 (s, 1H), 7.70 (d, J=0.5 Hz, 1H),7.59 (dd, J=5.3, 1.3 Hz, 1H), 4.39 (d, J=8.5 Hz, 1H), 4.19 (d, J=8.8 Hz,1H), 2.64 (s, 3H), 1.95-1.77 (m, 2H), 1.55 (dd, J=13.9, 4.9 Hz, 1H),1.43 (s, 3H), 1.39 (s, 9H), 1.00 (m, 6H), one exchangeable proton notobserved; LCMS (ESI) m/e 434.2 [(M+H)⁺, calcd C₂₃H₃₃ClN₃O₃, 433.2];LC/MS retention time (method B): t_(R)=2.07 min.

Part B:(S)-1-((4-chloro-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

TFA deprotection as described in Example 32. Obtained(S)-1-((4-chloro-2′-methyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(271.7 mg, 0.806 mmol, 81% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.59(d, J=5.3 Hz, 1H), 8.35 (s, 1H), 7.82 (s, 1H), 7.72-7.69 (m, 1H), 7.60(dd, J=5.3, 1.3 Hz, 1H), 3.97-3.90 (m, 2H), 2.64 (s, 3H), 1.83 (dt,J=12.7, 6.1 Hz, 1H), 1.53 (t, J=5.5 Hz, 2H), 1.28 (s, 3H), 1.04-0.96 (m,6H), two exchangeable protons not observed; LCMS (ESI) m/e 334.3[(M+H)⁺, calcd C₁₈H₂₅ClN₃O, 334.2]; LC/MS retention time (method B):t_(R)=1.49 min.

Example 239(S)-1-((4-chloro-6-(6-chloroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-1-((4,6-dichloropyridin-3-yl)oxy)-2,4-dimethylpentan-2-aminebis(2,2,2-trifluoroacetate)

TFA (2 mL, 26.0 mmol) was added a solution of (S)-tert-butyl(1-((4,6-dichloropyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(0.146 g, 0.387 mmol) in DCM (4 mL) at room temperature. The reactionwas stirred for 1.5 h at room temperature. The solvent was removed underreduced pressure and the crude material was carried on without furtherpurification. LCMS (ESI) m/e 259.9 [(M-NH₂)+, calcd C₁₂H₁₆C₁₂NO, 260.1];LC/MS retention time (method B): t_(R)=1.73 min.

Part B:(S)-1-((4-chloro-6-(6-chloroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Suzuki coupling was performed as described in Example 77, Part D.Obtained(S)-1-((4-chloro-6-(6-chloroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(8.4(S)-1-((4-chloro-6-(6-chloroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(mg, 0.020 mmol, 22% yield over two steps). ¹H NMR (500 MHz, DMSO-d₆) δ9.01 (d, J=4.4 Hz, 1H), 8.71 (s, 1H), 8.35 (d, J=2.2 Hz, 1H), 8.14 (d,J=9.2 Hz, 1H), 8.04 (s, 1H), 7.83 (dd, J=8.8, 2.2 Hz, 1H), 7.74 (d,J=4.4 Hz, 1H), 4.06 (s, 2H), 1.89-1.80 (m, 1H), 1.52-1.40 (m, 2H), 1.18(s, 3H), 0.95 (m, 6H), two exchangeable protons not observed; LCMS (ESI)m/e 403.8 [(M+H)⁺, calcd C₂₁H₂₄C2N₃O, 404.1]; LC/MS retention time(method B): t_(R)=1.91 min.

Example 240(S)-1-((2′,4-dichloro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((2′,4-dichloro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Suzuki coupling was performed as described in Example 77, Part D.Obtained (S)-tert-butyl(1-((2′,4-dichloro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(12.6 mg, 0.014 mmol, 7% yield). LCMS (ESI) m/e 476.1 [(M+Na)⁺, calcdC₂₂H₂₉Cl₂N₃₃Na, 476.2]; LC/MS retention time (method A): t_(R)=2.52 min.

Part B:(S)-1-((2′,4-dichloro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

TFA deprotection as described in Example 32. Obtained(S)-1-((2′,4-dichloro-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(4.9 mg, 0.014 mmol, 100% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.60 (s,1H), 8.51 (d, J=5.5 Hz, 1H), 8.44 (s, 1H), 8.15 (s, 1H), 8.08 (dd,J=5.1, 1.5 Hz, 1H), 1.82 (dquin, J=12.8, 6.4 Hz, 1H), 1.41 (t, J=5.3 Hz,2H), 1.14 (s, 3H), 0.93 (m, 6H), two exchangeable protons not observed;LCMS (ESI) m/e 337.0 [(M-NH₂)+, calcd C₁₇H₁₉C2N₂O, 337.1]; LC/MSretention time (method B): t_(R)=1.98 min.

Example 241(S)-1-((4-chloro-6-(7-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((4-chloro-6-(7-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Suzuki coupling was performed as described in Example 77, Part D.Obtained (S)-tert-butyl(1-((4-chloro-6-(7-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(30.5 mg, 0.021 mmol, 20% yield). LCMS (ESI) m/e 488.2 [(M+H)⁺, calcdC₂₆H₃₂ClFN₃O₃, 488.2]; LC/MS retention time (method B): t_(R)=2.37 min.

Part B:(S)-1-((4-chloro-6-(7-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

TFA deprotection as described in Example 32. Obtained(S)-1-((4-chloro-6-(7-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(4.4 mg, 0.011 mmol, 18% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.01 (d,J=4.4 Hz, 1H), 8.68 (s, 1H), 8.33 (dd, J=9.4, 6.4 Hz, 1H), 8.01 (s, 1H),7.85 (dd, J=10.5, 2.4 Hz, 1H), 7.66 (d, J=4.4 Hz, 1H), 7.60-7.53 (m,1H), 4.04 (s, 2H), 1.85 (dt, J=12.7, 6.5 Hz, 1H), 1.45 (t, J=6.4 Hz,2H), 1.18 (s, 3H), 0.96 (m, 6H), two exchangeable protons not observed;LCMS (ESI) m/e 388.1 [(M+H)⁺, calcd C₂₁H₂₄ClFN₃O, 388.2]; LC/MSretention time (method B): t_(R)=1.82 min.

Example 242(S)-1-((4-chloro-6-(7-(trifluoromethyl)quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((4,6-dichloropyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Prepared as described in Example 53, Part A. Obtained (S)-tert-butyl(1-((4,6-dichloropyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(765.6 mg, 2.03 mmol, 74% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ8.05-8.02 (m, 1H), 7.35 (s, 1H), 4.55 (s, 1H), 4.30 (d, J=8.8 Hz, 1H),4.11 (d, J=8.8 Hz, 1H), 1.91-1.75 (m, 2H), 1.58-1.48 (m, 1H), 1.41-1.38(m, 12H), 0.98 (m, 6H). LCMS (ESI) m/e 399.0 [(M+Na)⁺, calcdC₁₇H₂₆C2NaN₂O₃, 399.1]; LC/MS retention time (method B): t_(R)=2.41 min.

Part B: (S)-tert-butyl(1-((6-(7-fluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Suzuki coupling was performed as described in Example 77, Part D.Obtained (S)-tert-butyl(1-((6-(7-fluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(26.3 mg, 0.049 mmol, 33% yield). LCMS (ESI) m/e 538.1 [(M+H)⁺, calcdC₂₇H₃₂ClF₃N₃O₃, 538.2]; LC/MS retention time (method B): t_(R)=2.51 min.

Part C:(S)-1-((4-chloro-6-(7-(trifluoromethyl)quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine

TFA deprotection as described in Example 32. Obtained(S)-1-((4-chloro-6-(7-(trifluoromethyl)quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine(17.7 mg, 0.040 mmol, 83% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.14 (d,J=4.3 Hz, 1H), 8.69 (s, 1H), 8.49 (d, J=8.5 Hz, 1H), 8.45 (s, 1H), 8.06(s, 1H), 7.90 (d, J=8.9 Hz, 1H), 7.85 (d, J=4.6 Hz, 1H), 4.04 (s, 2H),1.85 (dt, J=12.5, 6.3 Hz, 1H), 1.45 (t, J=5.8 Hz, 2H), 1.18 (s, 3H),0.95 (m, 6H), two exchangeable protons not observed; LCMS (ESI) m/e438.3 [(M+H)⁺, calcd C₂₂H₂₄ClF₃N₃O, 438.1]; LC/MS retention time (methodA): t_(R)=1.66 min.

Example 243(S)-1-((4-chloro-2′,3′-dimethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (S)-tert-butyl(1-((4-chloro-2′,3′-dimethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Suzuki coupling was performed as described in Example 77, Part D.Obtained (S)-tert-butyl(1-((4-chloro-2′,3′-dimethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(23 mg, 0.014 mmol, 7% yield). LCMS (ESI) m/e 448.2 [(M+H)⁺, calcdC₂₄H₃₅ClN₃O₃, 448.2]; LC/MS retention time (method B): t_(R)=2.14 min.

Part B:(S)-1-((4-chloro-2′,3′-dimethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

TFA deprotection as described in Example 32. Obtained(S)-1-((4-chloro-2′,3′-dimethyl-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine(1.5 mg, 4.14 □mol, 8% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.46 (d,J=5.1 Hz, 1H), 8.42 (s, 1H), 7.46 (s, 1H), 7.28 (br. s., 1H), 4.08 (br.s., 2H), 2.57 (s, 3H), 2.07 (s, 3H), 1.61 (br. s., 1H), 1.43-1.25 (m,2H), 1.15 (br. s., 3H), 0.91-0.66 (m, 6H), two exchangeable protons notobserved; LCMS (ESI) m/e 348.2 [(M+H)⁺, calcd C₁₉H₂₇ClN₃O, 348.2]; LC/MSretention time (method B): t_(R)=1.34 min.

Example 244(S)-1-((5-(difluoromethyl)-2′-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine

Suzuki reaction was performed as described in Example 193. Obtained(S)-1-((5-(difluoromethyl)-2′-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine(9.8 mg, 0.028 mmol, 49% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.76 (s,1H), 8.50 (d, J=5.2 Hz, 1H), 8.33 (s, 1H), 7.66 (s, 1H), 7.57 (d, J=4.9Hz, 1H), 7.28 (t, J=1.0 Hz, 1H), 4.19 (s, 2H), 1.85 (s, 3H), 1.82-1.73(m, 1H), 1.44 (qd, J=13.9, 5.5 Hz, 2H), 1.16 (s, 3H), 0.92 (d, J=6.7 Hz,3H), 0.89 (d, J=6.4 Hz, 3H); LCMS (ESI) m/e 333.2 [(M-NH₂)+, calcdC₁₉H₂₃N₂F₂O, 333.2]; LC/MS retention time (method B): t_(R)=1.46 min.

Example 245(R)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-(difluoromethyl)-[3,4′-bipyridin]-2′-yl)carbamate

Suzuki coupling was performed as described in Example 77, Part D.Obtained (R)-methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-(difluoromethyl)-[3,4′-bipyridin]-2′-yl)carbamate(13.3 mg, 0.032 mmol, 54% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.69 (s,1H), 8.35 (d, J=5.1 Hz, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 7.44 (d, J=3.7Hz, 1H), 7.39-7.14 (t, J=44.0 Hz, 1H), 4.15 (d, J=2.6 Hz, 2H), 3.71 (s,3H), 1.84-1.73 (m, 1H), 1.40 (t, J=6.1 Hz, 2H), 1.13 (s, 3H), 0.92 (m,6H); LCMS (ESI) m/e 392.2 [(M-NH₂)+, calcd C₂₀H₂₄F₂N₃O₃, 392.2]; LC/MSretention time (method B): t_(R)=1.70 min.

Example 246(R)-1-((3-(difluoromethyl)-5-(quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Part A:(R)-1-((5-bromo-3-(difluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Prepared as described in Example 193. Obtained(R)-1-((5-bromo-3-(difluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(275 mg, 0.465 mmol, 55% yield). LCMS (ESI) m/e 320.1 [(M-NH₂)+, calcdC₁₃H₁₇BrF₂NO, 320.1]; LC/MS retention time (method B): t_(R)=1.95 min.

Part B:(R)-1-((3-(difluoromethyl)-5-(quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Suzuki coupling was performed as described in Example 77, Part D.Obtained(R)-1-((3-(difluoromethyl)-5-(quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(6.3 mg, 0.016 mmol, 24% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.98 (d,J=4.4 Hz, 1H), 8.52 (s, 1H), 8.16-8.12 (m, 2H), 7.87-7.80 (m, 2H),7.69-7.62 (m, 1H), 7.56 (d, J=4.4 Hz, 1H), 7.29 (t, J=1.0 Hz, 1H), 4.19(s, 2H), 1.87-1.78 (m, 1H), 1.49-1.38 (m, 2H), 1.16 (s, 3H), 0.94 (m,6H), two exchangeable protons not observed; LCMS (ESI) m/e 386.2[(M+H)⁺, calcd C₂₂H₂₆F₂N₃O, 386.2]; LC/MS retention time (method B):t_(R)=1.65 min.

Example 247(R)-1-((3-(difluoromethyl)-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Suzuki coupling was performed as described in Example 77, Part D.Obtained(R)-1-((3-(difluoromethyl)-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(7.7 mg, 0.022 mmol, 37% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.12 (s,1H), 8.77 (d, J=5.1 Hz, 1H), 8.68 (s, 1H), 7.98 (d, J=5.5 Hz, 1H),7.42-7.16 (t, J=55.0 Hz, 1H), 4.18 (s, 2H), 2.69 (s, 3H), 1.85-1.75 (m,1H), 1.41 (dd, J=9.0, 5.7 Hz, 2H), 1.14 (s, 3H), 0.92 (m, 6H); LCMS(ESI) m/e 334.1 [(M-NH₂)+, calcd C₁₈H₂₂F₂N₃O, 334.2]; LC/MS retentiontime (method B): t_(R)=1.81 min.

Example 248(R)-1-((3-(difluoromethyl)-5-(5,7-difluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Suzuki coupling was performed as described in Example 77, Part D.Obtained(R)-1-((3-(difluoromethyl)-5-(5,7-difluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(8.4 mg, 0.020 mmol, 21% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.02 (d,J=4.4 Hz, 1H), 8.44 (s, 1H), 8.12 (br. s., 1H), 7.81 (d, J=9.2 Hz, 1H),7.61 (ddd, J=12.3, 9.5, 2.4 Hz, 1H), 7.52 (d, J=4.8 Hz, 1H), 7.40-7.14(t, J=55.0 Hz, 1H), 4.16 (s, 2H), 1.86-1.77 (m, 1H), 1.42 (dd, J=7.9,5.7 Hz, 2H), 1.15 (s, 3H), 0.94 (m, 6H); LCMS (ESI) m/e 405.1 [(M-NH₂)+,calcd C₂₂H₂₁F₄N₂O, 405.2]; LC/MS retention time (method B): t_(R)=2.01min.

Example 249(R)-1-((5-(7-chloroquinolin-4-yl)-3-(difluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine

Suzuki coupling was performed as described in Example 77, Part D.Obtained(R)-1-((5-(7-chloroquinolin-4-yl)-3-(difluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine(16.9 mg, 0.039 mmol, 34% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.01 (d,J=4.4 Hz, 1H), 8.52 (s, 1H), 8.19 (d, J=2.2 Hz, 1H), 8.16 (s, 1H), 7.87(d, J=9.2 Hz, 1H), 7.69 (dd, J=9.2, 2.2 Hz, 1H), 7.60 (d, J=4.4 Hz, 1H),7.42-7.16 (t, J=55.0 Hz, 1H), 4.19 (s, 2H), 1.85-1.77 (m, 1H), 1.49-1.37(m, 2H), 1.16 (s, 3H), 0.94 (m, 6H); LCMS (ESI) m/e 403.1 [(M-NH₂)+,calcd C₂₂H₂₂ClF₂N₂O, 403.1]; LC/MS retention time (method B): t_(R)=1.97min.

Example 250N-(4′-((2-amino-2,4-dimethylpentyl)oxy)-3′-methyl-[1,1′-biphenyl]-3-yl)acetamide

Part A: Benzyl(1-(4-bromo-2-methylphenoxy)-2,4-dimethylpentan-2-yl)carbamate

Prepared as described in Example 29, Part A. Obtained benzyl(1-(4-bromo-2-methylphenoxy)-2,4-dimethylpentan-2-yl)carbamate (33 mg,0.076 mmol, 27% yield). LCMS (ESI) m/e 456.1 [(M+Na)⁺, calcdC₂₂H₂₈BrNO₃Na, 456.1]; LC/MS retention time (method B): t_(R)=2.55 min.

Part B: Benzyl(1-((3′-amino-3-methyl-[1,1′-biphenyl]-4-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Suzuki reaction was performed as described in Example 193. Obtainedbenzyl(1-((3′-amino-3-methyl-[1,1′-biphenyl]-4-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(21.1 mg, 0.047 mmol, 62% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ7.38-7.29 (m, 7H), 7.21 (t, J=7.8 Hz, 1H), 6.99-6.94 (m, 1H), 6.88 (t,J=1.9 Hz, 2H), 6.65 (ddd, J=7.9, 2.3, 0.9 Hz, 1H), 5.06 (s, 2H), 4.93(s, 1H), 4.13 (d, J=8.8 Hz, 1H), 3.99 (d, J=8.8 Hz, 1H), 3.73 (br. s.,2H), 2.28 (s, 3H), 1.92-1.77 (m, 2H), 1.72-1.65 (m, 1H), 1.48 (s, 3H),0.98 (m, 6H); LCMS (ESI) m/e 447.5 [(M+H)⁺, calcd C₂₈H₃₅N₂O₃, 447.6];LC/MS retention time (method A): t_(R)=2.38 min.

Part C: Benzyl(1-((3′-acetamido-3-methyl-[1,1′-biphenyl]-4-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate

Acetyl chloride (1 drop) was added to a solution of benzyl(1-((3′-amino-3-methyl-[1,1′-biphenyl]-4-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(0.0221 g, 0.049 mmol) in CH₂Cl₂ (2 mL) at room temperature. Thereaction was stirred for 10 min at room temperature before addition oftriethylamine (1 drop). The reaction was stirred for 2 h theconcentrated under reduced pressure. The residue was carried on withoutfurther purification. LCMS (ESI) m/e 489.5 [(M+H), calcd C₃₀H₃₇N₂O₄,489.3]; LC/MS retention time (method A): t_(R)=2.39 min.

Part D:N-(4′-((2-amino-2,4-dimethylpentyl)oxy)-3′-methyl-[1,1′-biphenyl]-3-yl)acetamide

A mixture of Pd/C (3 mg, 2.82 μmol) and benzyl(1-((3′-acetamido-3-methyl-[1,1′-biphenyl]-4-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate(23.94 mg, 0.049 mmol) in ethanol (3 mL) was hydrogenated via a H₂balloon at room temperature overnight. The reaction was filtered througha celite pad and washed with DCM. The filtrate was concentrated and theresidue was purified by reverse phase Prep HPLC. ObtainedN-(4′-((2-amino-2,4-dimethylpentyl)oxy)-3′-methyl-[1,1′-biphenyl]-3-yl)acetamide(11.4 mg, 0.031 mmol, 64% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 9.99 (s, 1H), 7.82 (s, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.41-7.24(m, 4H), 6.98 (d, J=8.5 Hz, 1H), 3.72 (d, J=3.1 Hz, 2H), 2.26 (s, 3H),2.07 (s, 3H), 1.85-1.78 (m, 1H), 1.46-1.41 (m, 2H), 1.16 (s, 3H), 0.93(t, J=6.3 Hz, 6H); LCMS (ESI) m/e 338.4 [(M-NH₂)+, calcd C₂₂H₂₈NO₂,338.2]; LC/MS retention time (method A): t_(R)=2.03 min.

Biological Data

Methods

AAK1 Kinase Assay

The assays were performed in U-bottom 384-well plates. The final assayvolume was 30 μl prepared from 15 μl additions of enzyme and substrates(fluoresceinated peptide (5-FAM)-Aha-KEEQSQITSQVTGQIGWR-NH2 and ATP) andtest compounds in assay buffer (10 mM Tris-HCL pH 7.4, 10 mM MgCl₂,0.01% Tween-20 and 1.0 mM DTT). The reactions were initiated by thecombination of bacterially expressed, GST-Xa-hAAK1 with substrates andtest compounds. The reactions were incubated at room temperature for 3hours and terminated by adding 60 μl of 35 mM EDTA buffer to eachsample. The reactions were analyzed on the Caliper LabChip 3000(Caliper, Hopkinton, Mass.) by electrophoretic separation of thefluorescent substrate and phosphorylated product. Inhibition data werecalculated by comparison to EDTA quenched control reactions for 100%inhibition and vehicle-only reactions for 0% inhibition. The finalconcentration of reagents in the assays are ATP, 22 μM;(5-FAM)-Aha-KEEQSQITSQVTGQIGWR-NH12, 1.5 μM; GST-Xa-hAAK1, 3.5 nM; andDMSO, 1.6%. Dose response curves were generated to determine theconcentration required inhibiting 50% of kinase activity (IC₅₀).Compounds were dissolved at 10 mM in dimethylsulfoxide (DMSO) andevaluated at eleven concentrations. IC₅₀ values were derived bynon-linear regression analysis. Results are shown in Table 1.

TABLE 1 AAK1 IC₅₀ Example (nM) 1 2.7 2 3.0 3 0.30 4 2.8 5 0.50 6 0.47 70.42 8 0.53 9 — 10 10 11 3.3 12 1.6 13 1.1 14 0.87 15 0.81 16 6.6 17 2418 5.0 19 0.36 20 0.34 21 0.74 22 0.65 23 0.76 24 0.63 25 1.0 26 0.69 271.0 28 1.2 29 0.67 30 1.4 31 4.5 32 4.5 33 0.32 34 15 35 0.77 36 0.89 370.51 38 0.79 39 3.2 40 8.7 41 3.8 42 3.3 43 0.64 44 2.8 45 1.2 46 0.8647 0.77 48 4.6 49 2.6 50 0.38 63 24 64 1.1 65 42 66 0.65 67 4.7 68 2.669 0.76 70 2.3 71 0.55 72 0.53 73 0.51 74 0.07 75 34 76 1.7 77 0.92 780.49 79 16 80 19 81 7.8 82 0.85 83 1.8 84 2.2 85 0.32 86 1.2 87 0.87 880.46 89 0.66 90 2.6 91 12.1 92 5.4 93 33 94 4.7 95 39 96 3.0 97 142 9810 99 31 100 6.8 101 27 102 1.3 103 0.68 104 0.83 105 0.72 106 0.62 10750 108 106 109 340 110 3.5 111 650 112 970 113 43 114 1400 115 13 1160.93 117 1.0 118 0.85 119 3.2 120 0.51 121 0.30 122 0.51 123 2.2 124 1.2125 1.6 126 0.80 127 6.2 128 3.5 129 1.4 130 1.4 131 0.82 132 1.5 1330.92 134 4.4 135 3.5 136 4.8 137 27 138 35 139 0.77 140 470 141 1.8 1424.1 143 0.45 144 1.3 145 0.24 146 0.19 147 0.56 148 0.34 149 1.5 150 24151 152 0.68 153 1.9 154 6.8 155 57 156 110 157 19 158 5.4 159 1.5 1600.8 161 1.7 162 530 163 1100 164 254 165 21 166 20 167 1040 168 58 169101 170 285 171 48 172 1295 173 42 174 54 175 17 176 53 177 8.7 178 150179 2.0 180 24 181 1.9 182 8.7 183 8.8 184 3.3 185 66 186 18 187 2.2 18892 189 0.49 190 1.2 191 0.99 192 9.6 193 2.9 194 1.5 195 0.25 196 0.20197 0.31 198 2.2 199 1.0 200 1.2 201 0.64 202 3.1 203 21 204 0.23 2050.70 206 4.3 207 19 208 4.6 209 21 210 79 211 491 212 1024 213 22 2140.86 215 197 216 25 217 0.56 218 1.0 219 0.59 220 0.38 221 4.1 222 1.2223 0.88 224 1.1 225 0.74 226 0.93 227 0.93 228 22 229 1.0 230 1.1 2310.47 232 0.41 233 0.73 234 3.2 235 0.36 236 0.98 237 1.4 238 2.1 2390.39 240 2.2 241 0.86 242 1.9 243 1071 244 262 245 11 246 26 247 234 24874 249 27 250 659 251 1098AAK1 Knockout Mice

Mice homozygous (−/−) for the disruption of the AAK1 gene were preparedby two methods; gene trapping and homologous recombination.

Gene trapping is a method of random insertional mutagenesis that uses afragment of DNA coding for a reporter or selectable marker gene as amutagen. Gene trap vectors have been designed to integrate into intronsor genes in a manner that allows the cellular splicing machinery tosplice vector encoded exons to cellular mRNAs. Commonly, gene trapvectors contain selectable marker sequences that are preceded by strongsplice acceptor sequences and are not preceded by a promoter. Thus, whensuch vectors integrate into a gene, the cellular splicing machinerysplices exons from the trapped gene onto the 5′ end of the selectablemarker sequence. Typically, such selectable marker genes can only beexpressed if the vector encoding the gene has integrated into an intron.The resulting gene trap events are subsequently identified by selectingfor cells that can survive selective culture.

Embryonic stem cells (Lex-1 cells from derived murine strain A129), weremutated by a process involving the insertion of at least a portion of agenetically engineered vector sequence into the gene of interest, themutated embryonic stem cells were microinjected into blastocysts whichwere subsequently introduced into pseudopregnant female hosts andcarried to term using established methods. See, e.g., “MouseMutagenesis”, 1998, Zambrowicz et al., eds., Lexicon Press, TheWoodlands, Tex. The resulting chimeric animals were subsequently bred toproduce offspring capable of germline transmission of an allelecontaining the engineered mutation in the gene of interest.

AAK1-gene disrupted mice were also made by homologous recombination. Inthis case, the second coding exon of the murine AAK1 gene (see GenBankAccession Number NM_177762) was removed by methods known in the art.See, e.g., U.S. Pat. Nos. 5,487,992, 5,627,059, and 5,789,215.

Mice homozygous (−/−) for the disruption of the AAK1 gene were studiedin conjunction with mice heterozygous (+/−) for the disruption of theAAK1 gene, and wild-type (+/+) litter mates. During this analysis, themice were subject to a medical work-up using an integrated suite ofmedical diagnostic procedures designed to assess the function of themajor organ systems in a mammalian subject. Homozygous (−/−) “knockout”mice were studied in conjunction with their heterozygous (+/−) andwild-type (+/+) litter mates. Disruption of the AAK1 gene was confirmedby Southern analysis. Expression of the murine homolog of AAK1 wasdetected by RT-PCR in murine brain; spinal cord; eye; thymus; spleen;lung; kidney; liver; skeletal muscle; bone; stomach, small intestine andcolon; heart; adipose; asthmatic lung; LPS liver; blood; banded heart;aortic tree; prostate; and mammary gland (5 week virgin, mature virgin,12 DPC, 3 day post-partum (lactating), 3 day post-weaning (earlyinvolution), and 7 day post-weaning (late involution)).

AAK1 homozygous (−/−) and their wild-type (+/+) littermates were testedusing the formalin paw test in order to assess their acute and tonicnociceptive responses. For these tests, Automatic Nociception Analyzers(purchased from the Ozaki lab at University of California, San Diego)were used. A metal band was placed around the left hind paw of eachmouse 30 minutes prior to testing. After the 30-minute acclimationperiod, 20 μl of 5% formalin is subcutaneously injected in the dorsalsurface of the left hind paw. Mice were individually housed incylindrical chambers for 45 minutes. Fresh 5% formalin solution wasprepared by diluting formaldehyde (Formalde-fresh 20%, FisherScientific, Fair Lawn, N.J.) with distilled water. Investigatorycompounds were administered 30 minutes prior to formalin injection.

A computer recorded flinches per minute, total flinches for phase I(acute phase=first 8 minutes), and total flinches for phase II (tonicphase=time between minutes 20-40) through an electromagnetic field. SeeYaksh T L, Ozaki G, McCumber D, Rathbun M, Svensson C, Malkmus S, YakshM C. An automated flinch detecting system for use in the formalinnociceptive bioassay. J Appl Physiol., 2001; 90:2386-402. As shown inFIG. 1, phase 1 and phase 2 data were obtained using homozygous (−/−)mice females (n=16), wild-type females (n=15), homozygous (−/−) micemales (n=9), and wild-type males (n=18). In all groups and in bothphases, the AAK1 homozygous (−/−) mice exhibited significantly lessrecorded paw flinching than their wild-type (+/+) littermates.

It will be evident to one skilled in the art that the present disclosureis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

The invention claimed is:
 1. A method for treating or managing a diseaseor a disorder mediated by AAK1 activity, the method comprisingadministering to a patient in need thereof a therapeutically effectiveamount of(S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine,or a pharmaceutically acceptable salt thereof, and a glucocorticoid,wherein the disease or disorder mediated by AAK1 activity is pain. 2.The method of claim 1, wherein the glucocorticoid is dexamethasone.